Human Function Block 1 Exam

What are the three divisions of the autonomic nervous system?

1. Enteric - controls GI system (self-contained system, but can be modulated by sympathetic and parasympathetic) 2. Sympathetic (flight or fight) 3. Parasympathetic (rest and digest)

From using the equation for potential recorded at the surface, what two values is the magnitude of this potential affected by?

1. Inverse square of the distance (1/r2) between the cardiac dipole and the measurement point 2. Angle (alpha) between the cardiac dipole and the measurement point

What are the three amino acids that mostly compose collagen and elastin?

Gly, Ala, and Pro Every 3rd AA is Gly residue for collagen No ordered structure in elastin

What enzyme is responsible for breaking down glycogen? How is it regulated?

Glycogen Phosphorylase -- Non-covalent allosteric regulation that shows sigmoidal-shaped curve on v0 vs. [S] plot. This enzyme has two active sites that communicate with each other, resulting in positive cooperativity in substrate Pi binding (similar to O2 binding). Also, the enzyme exhibits allosteric regulation with ATP, Glucose 6-P, AMP, and covalent post-translational modification using a serine residue.

What does the P wave represent in ECG?

P wave represents depolarization of the atria.

What does the PR segment represent in ECG?

PR segment is the time between the end of atrial depolarization and the start of ventricular polarization. It is a flat area or an area of zero potential on the recording. It represents depolarization of the AV node and Purkinje fibers, but this is small and not noticed by ECG.

What is the name of the drug used to inhibit transpeptidase (enzyme that forms cross-links in peptidoglycan)?

Penicillin -- active site serine attacks carbonyl C of drug and acyl-intermediate is formed. This breaks the lactam bond found on penicillin. In addition, penicillin irreversibly inhibits the transpeptidase.

Describe the four phases for SA node action potential.

Phase 0 - depolarization (slower than ventricular) Phase 1-3 - repolarization phases Phase 4 - depolarization ensues, in contrast to phase 4 resting membrane potential in ventricular AP.

Describe the five phases for ventricular action potential.

Phase 0 - rapid depolarization Phase 1 - rapid repolarization Phase 2 - partial repolarization where Vm attains a plateau phase Phase 3 - slow repolarization where Vm attains its MDP (Maximum Diastolic Potential) Phase 4 - negative Vm that resembles action potential

What enzyme hydrolyzes phospholipids and glycerophospholipids?

Phospholipase

How does glycogen phosphorylase modulate its activity with covalent modification (phosphorylation)?

Phosphorylation is signaled by epinephrine. Two specific serine residues are phosphorylated by a kinase which stabilizes the high-activity form. Phosphate groups can be removed using phosphatase when high activity is no longer needed.

Describe the beta-sheet.

Pleated shape of proteins that form hydrogen bonds between C=O and N-H groups. Usually in anti-parallel formation since it optimizes H-bonds increasing stability.

What are ABC Transporters?

Superfamily of ATP-binding cassette (ABC) transporter that catalyze primary active transport of a wide variety of molecules. They are required for lipid and sterol transport and the flippase enzyme necessary for moving lipid molecules from one membrane leaflet to the other. (CSTR type of ABC transporter)

Where does vitamin K come from in the human body?

Vitamin K is digested in the intestines and travels to the liver.

What are the two equations used to measure delta G (free energy)?

delta G = delta H -T*delta S = delta Go +RT*ln(K) K - mass action constant (not at equilibrium) delta Go - free energy change at standard conditions

What are the steps for synthesis and secretion of protein hormones from cells?

1. "Pre" portion (signaling portion) synthesized first from translation and provides signal that ribosomal complex complex should be transported and attached to RER. Rest of synthesis occurs so new protein is eventually extruded in RER. 2. "Pre" segment is cleaved off in RER and prohormone transported in vesicles to Golgi 3. Post-translational modification and vesicle packaging in Golgi 4. Pro-segment cleaved either in vesicles or Golgi 5. Vesicles migrate to inner surface of plasma membrane 6. Exocytosis of vesicles with hormones with an increase in intracellular calcium concentration as trigger

What is the secondary messenger sequence for synthesis of cAMP using G-proteins?

1. 7-TM receptor receives extracellular signal 2. Gs-protein binds to intracellular portion of the receptor 3. Binding triggers replacement of GDP with GTP 4. Activated alpha-GTP binds to a stimulates adenyl cyclase until GTP converted to GDP 5. Adenyl cyclase converts ATP to cAMP 6. cAMP binds to protein kinase increasing its activity 7. Enzyme then phosphorylates a specific set of proteins, altering their activity and producing the biological effect. (PK activated by cAMP also know as PKA). 8. Signal terminated by phosphodiesterase (cAMP to AMP) or protein phosphatase

What are the 3 main functions of thrombrocytes (platelets) in coagulation?

1. Adhesion -- glycoproteins in the platelet membrane bind collagen, vWF, and fibrin 2. Activation -- secrete ADP, Factor XIII, Factor V, growth factors, thromboxane A2, and which activate more platelets 3. Aggregation -- platelets aggregate

What are the two hormones of the Pro-opiomelamocortin family (from Anterior Pit.) and what are their targets? What are these hormones bio-synthetically or structurally related?

1. Adrenalcorticotropin (ACTH) -- Adrenal cortex 2. beta-Endorphins 3. Melonocyte Stimulating Hormone (MSH) -- Skin (melanocytes) Related by biosynthetic pathway rather than by structural homologies. All are derived from POMC peptide; however, biological functions differ between each one.

What are the five steroid-like hormones commonly used in the body and derived from cholesterol?

1. Aldosterone: Mineralcorticoid 2. Cortisol: Glucocorticoid 3. Testosterone: Androgen 4. Estrogen (or Estrodiol): Sex Hormone 5. Progesterone

What are the two types of facilitated diffusion?

1. Carrier-mediated Diffusion (like GLUT) GLUT 2 - liver transport: transports glucose out liver during fasting and in after a meal (Glukinase high then low while Hexokinase high most of time) 2. Ion Channels High transport rate and direction always down concentration gradient. They can open and close in response to chemical (ligand-gated) or electrical (voltage-gated) signals. Examples are Na+ and K+ channels along with aquaporins (bidirectional of transport water)

What are the steps involved with synthesis and secretion of steroid hormones from cell?

1. Cholesterol taken up from blood via LDLs (Low density lipoproteins) 2. Biosynthesis first occurs in mitochondria, so need StAR transport protein to get cholesterol inside (StAR- Steroidogenic Acute Regulator protein) -- RATE LIMITING STEP 3. Steroid hormones synthesized in mitochondria, cell-specific expression of key enzymes determines which steroid are produced 4. Shuttling -- biosynthetic enzymes in mitochondria and smooth ER used to shuttle intermediates back and forth for final hormone 5. Secretion of steroid hormone from mitochondria and cell

What are three inhibitors that alter ACh binding to its receptor?

1. Curare (reversible) - completely inhibits ACh receptor binding 2. Succinylcholine (reversible) - high binding affinity for ACh receptors but is not hydrolyzed 3. alpha-Bungarotoxin (irreversible) - binds to ACh receptor blocking all ACh interaction

What are two ways that can alter the release of ACh essentially inhibiting it?

1. Decreasing external calcium conc. 2. Botulinum toxin - poisonous protein that irreversibly binds to presynaptic nerve ending releasing its light chain that cleaves to docking proteins via proteolytic action preventing vesicular release of ACh.

What are three inhibitors that alter ACh destruction (can be inhibitor of acetylcholinesterase)?

1. Edrophonium (Tensilon) - Reversible acetylcholinesterase inhibitor: used in diagnosis of Myasthenia gravis. 2. Nerve gas, some insecticides - irreversible acetylcholinesterase inhibitors 3. DFP - diisopropylfluorophasphate (an organophosphate), interferes with ACh destruction resulting in respiratory paralysis

What is the signaling pathway for the second messenger cGMP?

1. Extracellular signal on 1-TM receptor induces endogenous guanlyl cyclase activity by making cGMP from GTP. 2. Nitric oxide (NO) diffuses across membrane to activate guanlyl cyclase which catalyzes the GTP to cGMP reaction. 3. cGMP activates a protein kinase (PKG) which can be used on proteins 4. Reset: NO can rapidly oxidize and cGMP-specific phosphodiesterases can convert cGMP to GMP

What are some examples of secondary active transport?

1. Gastric mucosal cells acidify stomach using H+/K+ ATPase to pump H+ out and K+ in. K+ high concentration in cell used to drive K+/Cl- symport 2. Mitochondrial transporter use H+ gradient developed during ox. phos. to transport H+ into mitochondria against its gradient (H+ gradient generated by redox reactions) 3. Active potentials in muscle and nerves

What are the 3 classes of membrane lipids? Which one of these is the most abundant?

1. Glycerophospholipids - most abundant polar lipid in membranes Contains glycerol, phosphate, and 2 fatty acids Examples of head grouped structures: Choline, Ethanolamine, Serine, Glycerol, Inositol (sugar molecule) 2. Sphingolipids - all spingolipids containsphingosine (18 carbons) Modified Sphingolipids: ceramides, sphingomyelin (phosphatidylcholine), cerebrosides (plus a simple sugar), gangliosides (plus complex sugar; with sialic acid called NANA) 3. Cholesterol - required for fluidity in membranes Synthesized from isoprene (is an isoprenoid) and large & rigid (amphipathic)

What are the 3 families of hormones the come from the pituitary gland?

1. Glycoprotein family 2. Somatomammotropin family 3. Pro-opiomelamocortin family

What are the two hormones of the somatommotropin family (from Anterior Pit.) and what are their targets? What are these hormones bio-synthetically or structurally related?

1. Growth Hormone (GH) -- Liver, muscle 2. Prolactin (PRL) -- Mammary Gland All derived from single ancestorial gene; aa homologous, include hCS

What are the two types of measurements used to quantitatively measure metabolism of hormones?

1. Half-life - time required for hormone concentration to fall to 50% (Can be seconds to days) 2. Clearance rate - volume of blood completely cleared of hormone/unit time (more accurate but more difficult to measure)

What are the four main classes of GAGs? Which one is the most prominent in the ECM?

1. Hyaluronic acid -- most prominent -- made in cytosol 2. Chrondroitin sulfate -- made in Golgi 3. Heparin sulfate -- made in Golgi -- most highly sulfated 4. Keratan sulfate -- made in ER High levels of hydration in GAGs(from many negative charged groups on disaccharides) give high capacity for cushioning and lubrication.

What are the three important features of the contractile process in the sarcomere?

1. Hydrolysis of ATP (ATP is energy source for contraction_ 2. Physical-chemical reaction phenomenon that is manifested in muscle shortening and tension development 3. Control by calcium such that depolarization, which travels down T-tubules, can cause release of Ca2+ from SR and activate contraction process.

What are the five components of ionic currents flowing in phase 2 for ventricular AP?

1. INA inactivation 2. Ito inactivation 3. Ica inactivation 4. Stimulation of Na-Ca exchanger (3 Na+ in for every 1 Ca2+ out). Decrease in calcium cause net inward current. 5. Ik activation, outward current (Ik = delay-rectifier)

What is the general sequence of the ADH primary system the controls blood osmolarity?

1. Increase in osmolarity is sensed by osmoreceptors in hypothalamus 2. These neurons send excitatory stimuli to ADH cell bodies, producing APs that travel down to Post Pit. and cause ADH release 3. ADH travels to the kidney via blood where it inhibits water intake 4. Increase in return of water dilutes blood returning to the status quo for blood osmolarity

What are the four general mechanisms for regulating enzyme activity and their relative time scales?

1. Long term regulation (change amount of enzyme) -- several hours 2. Non-covalent modification (short-term) -- minutes 3. Covalent modification (short-term) -- minutes 4. Genetic variation -- always : Slightly different forms of the enzyme (isozymes) are expressed in different tissues; they have different properties so different kinetics in other tissues

What are the steps for activation in enzyme-linked receptors (for tyrosine kinase)?

1. Messenger binds to receptors and causes them to dimerize 2. Receptor then auto-phosphorylates (one receptor phosphorylates the other) its intracellular portion which stabilizes its PK activity 3. PK enzyme then phosphorylates other proteins that produce effects

What are the six distinguishable anatomical features represented in skeletal muscle?

1. Muscle fibers - are the muscle cells, multinucleated 2. Sarcolemma - cell membrane of muscle cell 3. Myofibrils - each cell contains several hundred to several thousand myofibrils, composed of actin and myosin, filaments arranged into a sarcomere (A band - just actin, I band - just myosin) 4. Sarcoplasm - cytoplasm not related to the contractile process. Contains mitochondria, ribosomes, enzymes, electrolytes, and macromolecules (glycogen). Red to white muscle fibers greatest to least: cardiac, Type 1, Type 2 5. Sarcoplasmic Reticulum - specialization of ER found in muscle cells. Specialized role in calcium storage release. 6. T-tubule - transverse tubule is an invagination of the plasma membrane

What are the four major protein units in the sarcomere?

1. Myosin 2. Actin 3. Tropomyosin 4. Tropinin complex (3 seperate proteins)

What are the four major control systems in endocrinology?

1. Negative Feedback - most common in endocrine (80-90%) 2. Positive Feedback - continued increase of elements until broken by external factor 3. Feedforward System - increase in hormone levels in response to a specific signal; only operates when signal occurs (baby suckling on breaths --> oxytocin release) 4. Endocrine Rhythms - produce increase in hormone secretion at regular intervals. Daily changes (diurnal) are most common. (cortisol increase in morning with light)

What are the four different types of point mutations?

1. Neutral - no alteration in primary protein structure 2. Conservative - AA replaced by one with similar polarity, size, charge 3. Non-conservative - AA replaced with different size, polarity, or charge 4. Nonsense - codon is changed to a stop codon (truncation)

What are the amino acid derivative hormones (from tyrosine)?

1. Norepineprhine and epinephrine are catecholamines 2. Thyroxine (T4) and tri-iodothyronine (T3) in thyroid gland

What is the signaling pathway for the calcium-calmodulin second messenger system?

1. Outside signal increases calcium concentration intracellularly (like action potential does) 2. Intracellular calcium levels can directly cause exocytosis. Calcium binds to the protein known as Calmodulin (4 Ca2+ for one Cal). 3. Ca-Calmodulin activates CaM-dependent kinase (CM-K) 4. Proteins can be phosphorylated other proteins

What are two reasons that explain why the Hb binding curve is to the right of the Mb binding curve?

1. Present of low affinity T-form of Hb at low pO2 2. High concentration of 2,3 bisphosphoglycerate (2,3-BPG) in RBCs 2,3-BPG is a negative allosteric effector of O2 binding preferring the T-form, thus stabilizing deoxy-Hb.

What are the 3 stages of hemostasis, or repairing a lesion in the blood vessel?

1. Pro-coagulation, wherein formation of a clot is initiated 2. Anti-coagulation, during this time the process of pro-coagulation is inactivated 3. Thromboylsis - removal of clot after repairs have been completed

What composes the ECM of a cell typically?

1. Proteins (Type-1 Collagen, elastin, laminin, fibrillin, fibronectin, many other collagens but mostly Type-1) 2. GAGs (hyaluronin) - hyaluronin takes up most space 3. Proteoglycans (aggrecan and perlecan)

What are some parameters in SA nodes that control heart rate?

1. Rate of diastolic depolarization 2. MDP (more or less negative) 3. Membrane threshold 4. Rate of repolarization

What are the two effects of myelination has on the axon?

1. Reduces capacitance of the internodal region by increasing thickness of the dielectric 2. Increases the lateral resistance through the membranes of the internodal region, thus lateral current leakage through channels is reduced Conduction velocity of myelinated nerve fibers is linearly proportional to diameter

What is the activation sequence for the depolarization wave in the heart?

1. SA Node 2. Atrioventricular (AV) Node 3. Bundle of His 4. Purkinje Fibers 5. Working Ventricle

What is the secondary messenger sequence for the phosphatidylinositol system?

1. Same steps involved with G-protein system, except different enzyme involved 2. Phospholipase-C, enzyme that breaks down membrane phospholipid, phosphatidylinositol (PIP2) is activated by using Gq and alpha q. 3. Two products produced are diacylglycerol (DAG) and inositol triphosphate (IP3), both are secondary messengers 4. IP3 acts to increase intracellular calcium, DAG activates protein kinase-C (PKC) 5. PKC also stimulated by calcium. PKC will end up phosphorylating a protein.

What are variables that endplate potential is a function of?

EPP is a function of the probability of ACh molecules interacting with receptors and is both time- and concentration-dependent.

What are the three types of crosslinks that tropocollagen can form after they line up in a staggered array of insoluble collagen fibers? What enzyme oxidizes the Lys side chain converting a mine to an aldehyde?

1. Schiff Base - 1 aldehyde side chain reacts with 1 amine side chain 2. Reduced Schiff Base (Lysinorleucine) - when double bonds in Schiff Base are reduced 3. Aldol cross link - 2 lysine residues are oxidized to aldehydes and can form an aldol crosslink Enzyme that oxidizes Lys side chain is Lysine Oxidase. Cross-linking strengthens collagen fibers, but reduces flexibility.

What are the systems that the PNS controls primarily?

1. Sensory systems: Five specialized senses (sight, hearing, taste, smell, balance) Pain and temperature sensors in skin. Internal sensors (pain, blood pressure, CO2) part of ANS 2. Somatic motor system (skeletal muscle; interactions with external environment 3. Autonomic motor system (heart, smooth muscle, glands): controls internal environment

What are the 4 types of membrane transport? Which ones require ATP (directly or indirectly) and which ones require transmembrane proteins?

1. Simple diffusion -fast 2. Facilitated diffusion -can be fast 3. Primary active transport (direct)-slow 4. Secondary active transport (indirect)-slow 2-4 require transmembrane proteins.

What is the Hodgkin cycle? What is the opposite of this?

1. Stimulus causes a local depolarization 2. Some sodium channels open in response to the depolarization (voltage dependence), sodium conductance, Gna, increases 3. increased sodium conductance (more open channels) leads to more sodium influx 4. increased sodium influx leads to more depolarization So this basically is called the upstroke of action potential (positive feedback) to initiate an action potential. Opposite is downstroke of action potential (negative feedback). There are conductance changes that promote repolarization.

What two things are needed to stop coagulation?

1. Stopped activation of more thrombin 2. Removal of the high activity thrombin undergoes during coagulation

What are the four basic physiological functions of skeletal muscle?

1. Thermogenesis - maintenance of body temperature 2. Protein Stores - stores protein but also uses protein for many functions (to move, for cytoskeleton, fluid balance, etc.) 3. Psychological - body expressions, voluntary control over muscles 4. Biomechanical - muscle tissue can shock absorb converting chemical energy into mechanical energy

What are the three hormones of the glycoprotein family (from Anterior Pit.) and what are their targets? What are these hormones bio-synthetically or structurally related?

1. Thyroid-stimulating hormone (TSH) -- Thyroid 2. Luteinizing hormone (LH) -- Gonads 3. Follicle-stimulating hormone (FSH) -- Gonads All have the same alpha-subunit, different beta subunits, hCG is also a member of this family

What are the six hypophysiotropic hormones with their targets that I need to know for Goodman?

1. Thyrotropin-releasing hormone -- TSH (and PRL) 2. Gonadotropin-releasing hormone -- LH & FSH 3. Growth hormone-inhibiting hormone or Somatostatin -- GH (and TSH) 4. Growth hormone- releasing hormone -- GH (dominant) 5. Corticotropin-releasing hormone -- ACTH 6. Prolactin-inhibiting hormone -- PRL (inhibits lactation - production of milk in mammary glands) (dominant)

What are the 3 prejunctional events in the synaptic transmission of acetylcholine?

1. Transmitter Synthesis - ACh is synthesized from Acetyl-CoA and choline by the enzyme, choline acetylase, which is present in the nerve ending. This synthesis is energy-dependent and requires the mitochondria. 2. Packaging and supplying - ACh is transported from site of synthesis into the vesicles by proton-driven exchangers. Hydrogen ions are exchanged for ACh. This loads the vesicle with ACh. 3. Transmitter release - can be spontaneous or triggered release, but mostly triggered. When action potential arrives at presynaptic nerve terminal, there is a large conductance change for calcium. When calcium channels open, calcium flows into the presynaptic terminal and results in the secretion of ACh into the synaptic cleft by exocytosis. (SPECIFICS: Calcium binds to calmodulin kinase 2, phosphorylates Synapsin allowing vesicles to move along actin to docking sites SNAREs and SNAPs to begin membrane fusion. Calcium also binds to synaptotagmin to complete the membrane fusion resulting in ACh release.)

What are the components of the basal lamina?

1. Type-4 collagen (fibrous layer) 2. Laminin (forms scaffold and binds cells to basal lamina) 3. Perlecan (heperan sulfate-containing proteoglycan and can connect to laminin and entactin) 4. Entactin (binds laminin to collagen network)

What are the three major types of enzyme-catalyzed receptors and how are they different from each other?

1. Tyrosine Kinase Receptors - tyrosine is phosphorylated, receptor dimerization structurally similar 2. Serine/Threonine Kinase Receptors - serine or threonine phosphorylated, receptor dimerization occurs between two different receptors 3. Receptor-Associated Tyrosine Kinases or Cytokine receptors - similar to tyrosine kinases, except receptor doesn't have endogenous PK activity. A cytoplasmic kinase (Janus Kinase) binds to dimerized receptors activating JAK so that it phosphorylates the receptor and auto-phosphorylates itself. It can then phosphorylate other enzymes afterward.

What are the three plasminogen activators that can be used to initiate fibrinolysis? How can the process of fibrinolysis be regulated?

1. tPA 2. Urokinase 3. Steptokinase Fibinolyisis can be regulated by inactivation of tPA and plasmin by binding to their serpin proteins.

List 4 ways that enzymes lower the activation energy of reactions.

1.) Specific interactions between parts of enzyme active site and S will enhance catalytic activity 2.) Substrate is bound in close proximity to reactive parts of enzyme and with proper orientation to maximize probability of reaction. 3.) Formation of E-S complex decreases the entropy of the substrate, increasing its energy 4.) Tight binding of transition will lower transition-state energy, decreasing Ea

What are the 3 critical steps in cataylsis that occur in the enyzme active site.

1.) Substrate binding with high specificity 2.) Chemically transfrom substrate to product 3.) Release product from enzyme as enzyme is recycled

What is the name of HIV Reverse Transcriptase inhibitor?

3'-azidothymidine: converted to AZT-triphosphate by human kinase and terminates chain growth in cDNA. Like acyclovir, it lacks a 3'-OH group.

How is gamma-carboxyglutamate synthesized on coagulation factors using vitamin K?

A carboxyl group is attached to a glutamate residue via an oxidative carboxylation reaction. Vitamin K is a reducing cofactor that reducing CO2 to form a carboxylic acid group on the glutamate. Vitamin K is then recycled to be reduced back to active vitamin K from its epoxide form for another reaction.

What does a low Ki mean?

A low Ki for an enzyme means that the inhibitor for that enzyme has high potency (Ki = koff/kon).

What is I-cell disease characterized by?

A mutation in the enzyme that catalyzes the addition of mannose-6-phosphate to catabolic enzymes targeted to the lysosome can result in I-cell disease (protein targeting sequence disrupted). Results: macromolecules not degraded by lysosomes becoming large inclusion bodies that cause cell death and catabolic enzymes secreted to extracellular space.

What are the names of the two hormones produced by the posterior pituitary gland?

ADH (or Vasopressin) and Oxytocin ADH - Decreases water excretion Vasopressin - increases blood pressure Oxytocin - stimulates contraction mammary gland and uterine contraction

What are the two fuels used in generating energy in muscle cells?

ATP - essential molecule for muscle cells. Quantitatively different in different muscles CP (Creatine Phosphate) - major storage form of high energy-phosphates in muscle and greatly exceeds ATP amounts. Usually donates Pi to ADP to recycle ATP. Lasts up to 30 sec.

Some definitions from Yu: -Accommodation -Depolarization Block -Hyperpolarization Block -Pharmacological Block

Accommodation - slowly rising stimulus fails to elicit an action potential (sodium rises so slowly that inactivation can "catch up" Depolarization Block - persistent depolarization leads to persistent sodium inactivation Hyperpolarization Block - "distance" to threshold is increased; higher proportion of sodium activation gates in comparison to resting are shut Phramacological Block - anesthetics and toxins

What two molecules form acetylcholine in the neuron?

Acetyl-CoA and choline

What are the two major neurotransmitters used in parasympathetic and sympathetic activity for the heart?

Acetylcholine and Norepinephrine respectively

What is the key to how enzymes work when catalyzing reactions?

Activation energy is key aspect to the kinetics: the smaller the Ea, the faster the reaction.

Where do chemical reactions in the enzyme take place?

Active Site, determined by protein structure and contains key residues that participate in the reaction.

What are the two steps involved with the transpeptidase that assists in the formation of peptidoglycan?

Acylation - Serine protease acylates the carbonyl located on D-Ala residue at end of non-pentaglycine peptide. Deacylation - enzyme uses the terminal -NH2 of the pentaglycine as a nucleophile to deacylate enzyme. For this to work, water must be excluded from the active site.

What leads to hydrophobic mismatching in membrane proteins? How can these proteins adapt to hydrophobic mismatching?

Adaptability of membrane is limited, so when this adaptability is extended beyond limits, then there is a "hydrophobic mismatch". Hydrophobic mismatch can favor one conformation over another and thereby prevent conformational change required for function. This can be prevented by maintaining optimal thickness of the hydrophobic portion of the membrane to have appropriate match up with the transmembrane protein since membrane thickness is a biphasic quality (has an optimum value). Membrane thickness tuned based off lipid composition (length of head and FA chain in phospholipid).

Why are fibrin and thrombocytes both needed for coagulation?

Aggregated platelets alone are not strong enough to withstand the shear forces of blood. So, coating the platelet plug with the fibrous protein fibrin stabilizes the clot so it can survive until blood vessel repair.

Describe the structure of the alpha helix.

All peptide bonds point in the same direction in the helix (N-H bonds point toward N-terminus while C=O bonds point in C-terminus) R groups extend radially outward and can be hydrophilic, hydrophobic, or amphipathic. Proline can be used to destabilize hydrogen bonds in helix and to create a bend in the helix.

What are the two major classes of catecholamine receptors? What types of responses do the catecholamines elicit when they bind to these receptors?

Alpha - adrenergic: NE greater than E alpha 1: acts via DAG/IP3; contracts arterial blood vessels and some other smooth muscle alpha 2: lowers cAMP; in nerve terminals Beta receptors: Beta 1: limited to heart NE=E Beta 2: Some blood vessels, most smooth muscles, metabolic tissues, but causes vasodilation and relaxation E>NE Beta 3 in adipose, stimulate cAMP E>NE

What is the secondary structure that comprises most transmembrane protein domains in the plasma membrane.

Alpha-helices (but can have beta-sheet barrel structures)

How can HIV protease be inhibited?

An effective inhibitor to HIV protease would be one that mimics the transition state of the substrate. Using hydroxyethyl groups linking two groups with peptide bonds and bulky aromatic groups on either side to assist sticking in the active site could inhibit the protease.

What is the mechanism of the aspartate proteases?

Aspartate acts as a base to deprotonate water; the other protonates the tetrahedral intermediate to make it less stable. Thus, the intermediate is a tetrahedral and has a hydroxl group. Deprotonation of the hydroxyl group and protonation of the amine leaving group completes the catalytic cycle.

What molecule is responsible for irreversibly inhibiting cyclooxygenase, an enzyme used in for prostaglandin synthesis? What is the mechanism behind it?

Aspirin -- acetyl group on aspirin is transferred to Ser-530 of cyclooxygenase and prevents substrate interaction with catalytic tyrosine. Also, hydrophobic active site prevents hydrolysis of the ester bond between the acetyl group and serine.

How can aspirin decrease hypercoagulability? What other drug decrease coagulativity by imitating ADP?

Aspirin decreases hypercoagulability by irreversibly inhibiting the cyclooxygenase that produces thromboxane A2. Thromboxane A2 is a potent signaling molecule for platelet recruitment and aggregation. Another drug that can decrease coagulability is Plavix. The ADP receptor on platelet cell membranes can be targeted to decrease coagulability using Plavix since Plavix and ADP are both very negatively charged.

What two drugs can be used to treat organophosphorus poisoning?

Atropine and Pralidoxime -- Atropine is used to block acetylcholine signaling buying time to make new esterase molecules and pralidoxime interacts with inhibited enzyme and removes inhibitor.

How are ABC transporters involved in multi-drug resistance?

Bacteria can use ABC transporters to export peptides, lipids, ions, and antibiotics produced by other bacteria. One of the main sources of antibiotic resistance is drug efflux through ABC transporter. Exposure to sub-lethal dose of antibiotic can favor survival of bacteria that have genes for increased synthesis of drug-effux ABC transporter. Genes shared among bacteria can lead to resistance to multiple forms of antibiotics. Example: P-glycoprotein is mammalian ABC transporter that can catalyze effux of anti-cancer drugs. Resistance to chemotherapy can be from increased expression of P-glycoprotein in cancer cells. Drugs are exported at such a high rate that lethal dose can not be obtained.

What can cause elevated levels of bilirubin in blood?

Bilirubin is product of breakdown of heme. Thus, if there is an increase in bilirubin then more red blood cells must be breaking down leading to ischemia.

What does tetrodotoxin (TTX) do?

Blocks Na+ channels on cell membrane. However, blocking the majoring of Na+ channels would still not abolish an action potential.

What is the term for a random motion of the molecules in a solution?

Brownian motion

Why is AMP a regulator in glycogen phosphorylase?

Buildup of AMP indicates an energy deficient cell, so AMP will act as an allosteric activator for glycogen phosphorylase to breakdown glycogen to generate ATP from AMP.

How is a v0 vs. [S] curve generated?

By measuring v0 at many different [S] while keeping [E] constant

How do metalloproteinases (MMPs) become inhibited in tissues?

By removing the zinc ion (not a physiological method) or by blocking the active site. Active site needs water, so blocking this site can inhibit the enzyme.

What are the equations for chemical driving force (CDFx) and electrical driving force for ion species X? What is the electrical potential difference (also called Nernst potential) equation? How do both of these relate to the net driving force?

CDFx = (61/zx)*log([Xi]/[Xo]) at body temperature Vm = resting membrane potential = inside electrical potential - outside electrical potential Nernst Potential: Ex = -CDFx = (61/zx)*log([Xo]/[Xi]) This is potential difference that would completely counterbalance the CDFx such that there would be zero net ionic flux. Make sure to use correct zx: +1 for Na+, +2 for Ca2+, -1 for Cl- NDFx = Vm+CDFx = Vm-Ex If NDFx = 0, then at equilibrium condition (equal chemical/electrical forces between two sides)

How is calcium removed from the nerve terminal during the repolarization phase of the nerve (stops signaling release of neurotransmitters)?

Calcium is extruded by a sodium-calcium exchange mechanism (Na-Ca antiporter). Sodium on outside of cell is used as driving force to move calcium out of the cell.

What is the U wave in ECG?

Can be seen as a small wave right of the T wave that could represent the repolarization of the ventricular conduction network. Only present in some ECG recordings.

What determines catalytic activity in HIV protease?

Catalytic activity is determined by two aspartate residues. These residues are adjacent in the quaternary structure of the enzyme and work in concert to allow acid-base catalysis of proteolysis.

What causes the prion disease Mad-Cow?

Caused by accumulation of prion protein aggregates in brain cells. The beta-sheet conformation is proteolysis-resistant so this leads to aggregates that cause the disease. Also, the beta-sheet confirmation can act as a template to direct refolding of normal genotype to misfolded one.

What is the name of the enzymes that assist in protein folding?

Chaperones Types: HSP70 and HSP60 HSP60 - large complex that binds misfolded proteins and uses energy from ATP to catalyze unfolding/refolding. If this doesn't work, then proteosome will come to break down protein.

What are some other ways CFTR is inhibited other than proteolysis of CFTR protein from delta F508 (truncation mutation in gene)?

Cholera toxin in intestines prevents G-protein signaling from turning off, which prolongs stimulation of adenylate cyclase which increase cAMP concentrations. This causes CFTR to stay open flooding out Cl- from cell into lumen of intestine causing increased secretion of water to balance osmotic pressure. This leads to severe dehydration and diarrhea.

What are the two molecules that result when acetylcholine is removed by acetylcholine esterase, a serine protease?

Choline and Acetate -- Two step mechanism: 1. acylenzyme complex formed 2. Hydrolysis of intermediate

What are the three most common digestive serine proteases and what type of amino acids bind to their binding pockets?

Chymotrypsin -- Tyr (Aromatic and maybe aliphatic) Trypsin -- Arg (Basic) Elastase - Ala (small chain AA)

Malonate cannot be oxidized to form C-C double bond when in the active site of succinate dehydrogenase, but it can take the place of succinate which does oxidize to form fumarate. What type of inhibition is this?

Competitive Inhibition

With ions and action potentials, what increases in the Ohm's law equation to increase current during an action potential?

Conductance increases (specifically in sodium channels) delta Ina = delta Gna*NDFna . ---- results in depolarization Conductance increase in potassium channels would lead to hyperpolarization, or repolarization if after depolarization

Using the application behind tissue-specific isozymes, blood reports can now be used to diagnose heart attacks. What three enzymes/proteins can be measured in the blood as a MI marker?

Creatine Kinase (CK), Lactate Dehydrogenase (LDH), and Troponin (Tn). Specifically, CKmb, LDH1, and TnT2, all found in cardiac cells.

What are the genetics for cystic fibrosis?

Cystic fibrosis is autosomal recessive meaning that both copies of mutated allele are needed to manifest disease.

What may be the cause of elevated levels of homocysteine in blood and urine?

Deficiency in cystine metabolism (cofactors might be missing for enzymes that metabolize homocysteine to another molecule like methionine)

What causes maple-syrup urine disease (MSUD)?

Deficiency in the alpha-keto acid dehydrogenase prevents degradation of branched-chain amino acids. Results in elevated levels of valine, isoleucine, and leucine in the blood and urine.

How is membrane curvature altered in the plasma membrane?

Degree of curvature can be "tuned" by mixing lipids of different shape in each bilayer. Also, conical lipids will form bilayer with either positive curvature or negative curvature. Cylindrical lipids will form flat bilayer.

How can propagation velocity be increased in the nerve?

Depends on downstream "reach" of the local currents. Velocity rises when "reach" is increased by increasing the axial current relative to lateral current. This can be done by increasing number of voltage channels in the membrane. Also, increasing diameter raises axial current more than lateral current (axial resistance reduced). Propagation velocity proportional to SQRT(Diameter)

What processes in the body are serine proteases usually found in?

Digestion, blood-clotting, neutrophils, and others

How is Parkinson's disease characterized?

Disease that is characterized by protein aggregates (Lewy Bodies) in dopaminergic neurons of substantia nigra pars compacta (SNpc). Lewy bodies contain alpha-synuclein. Mutation of alpha-synuclein can favor aggregation which are resistant to proteolysis. Also, oxidation of dopamine may enhance toxic oligomer of alpha-synuclein. Lewy bodies produced from process may be protective mechanism to get rid of small oligomers.

Describe the Donnan effect.

Donnan effect - compartment containing the nonpermeant charged solutes develops a higher solute concentration and thus a higher osmotic pressure than the other compartment because the principle of bulk electroneutrality requires that an excess (in osmotic sense) of small ions shift to the compartment containing the nonpermeant ions (eg. blood contains more charged proteins than the interstitial fluid surrounding the capillaries. Osmotic force greater in blood than in interstitial fluid, but hydrostatic force also higher in blood due to heart, so balance of forces)

How does excitation-coupling in the myofibril work?

Excitation-coupling triggers the release of calcium from the lateral cisternae of the SR from the spread of the muscle action potential down the T-tubule. This allows a small diffusion distance between calcium and Troponin C. ATP is required to transport calcium back into SR (1 ATP for every 2 Ca2+)

What is the difference between exopeptidases and endopeptidases?

Exopeptidase - proteases that chop off N-terminal or C-terminal residues. Endopeptidase - proteases that cut peptide bonds in the interior of the polypeptide

What Factors are calcium dependent and need calcium to be activated?

Factors II, VII, IX, and X

What coagulation factors are involved in the extrinsic pathway?

Factors III and VII. Both of these factors together activate Factor X. Factors II, XII, trauma, and calcium activate VII to VIIa.

What factors are deficient in Hemophilia A and B? How are both of these Hemophilias clinically indistinguishable?

Factors VIII and IX respectively. Lack of vWF will also lead to deficiency in Factor VIII and thus insufficient fibrin activation. Since Factors VIII and IX work together to activate Factor X, Factor VIII must be measured individually to distinguish between them.

What factors are involved with the intrinsic pathway?

Factors XII, XI, IX, X. Factor VIII helps activate Factor X. Also, Factor VII from extrinsic pathway can help activate Factor IX (cross-talk between pathways to ensure adequate activation of Factor X and thrombin).

What allows membrane helices to pack together and still motion around to change conformation of transmembrane protein?

Few H-bonds and salt bridges since these bonds are very strong in the membrane and would lock protein in place if too many. (More Gly and Pro residues)

How is fibrin formation localized on to the platelet membrane? What post-translationally modified amino acid is responsible for this?

Fibrin formation is localized on to platelet membranes by binding calcium ions to the membrane and by binding gamma-carboxyglutamate to these ions. Factors II, VII, IX, and X have the gamma-carboxyglutamate, so they can bind to calcium ions located on the platelet membrane. Before this, platelet activation will transfer phosphatidyl-serine to the outer leaflet via a flippase for binding with calcium.

What are the differences between fibrous and globular proteins?

Fibrous proteins: extended linear structure and usually exist as large, insoluble aggregates (collagen and actin) Globular proteins: spherical shaped and soluble in aqueous solution (hemoglobin, trypsin)

What is Fick's Law of Diffusion? What doe the D term represent?

Fick's Law: J = -D*(delta C/delta X) D = uRT J is flux density (minus sign in equation indicates direction of flux is "downhill") D = diffusion constant T = absolute temperature

What is flux?

Flux is the rate of product formation by an enzyme (or pathway).

How is contractile protein chemistry translate to muscle strength and power?

Force, or tension, is an outcome of contractile protein interactions, so muscle strength is a function of the amount of protein in a myofiber and proportional to the cross-sectional area of the muscle. Power is also a function of contractile proteins being proportional to the speed of the ATPase reaction in myofibers. Increasing this reaction increases muscle velocity which increases power.

What effect do enzyme catalysis have on delta G and Ea?

Free-energy change (delta G) is independent of how reaction occurs and Ea is lowered for reactions catalyzed by enzymes.

What are some structural differences between Hb and Mb? What are some functional differences?

Hb: Located in RBCs, tetramer Mb: Located in muscle cells, single subunit Hb: transports O2 via RBCs from lungs to tissues, High affinity in lungs while low in tissues, cooperativity, 2 conformations, regulated by allosteric effects Mb: O2 storage in muscle, high affinity, hyperbolic curve (non-cooperative), single conformation, not regulated

What are two ways that inhibit the ACh synthesis at the terminal end of the neuron?

Hemicholinium can be used to block uptake of choline by the nerve terminal = decreased ACh synthesized Metabolic inhibitors blocking mitochondrial function can inhibit synthesis since it is an ATP-dependent reaction

Define hemostasis.

Hemostasis is the maintenance of the closed system of the circulatory system.

What is the role of Heparin in anti-coagulation?

Heparin is a highly negatively charged saccharide (GAG) that enhances the binding of the serpin antithrombin-3 and thrombin by acting as a scaffold. The serpin will irreversibly inhibit thrombin. There are also serpins for Factors IXa and Xa.

How can the herpes simplex infection be treated? How can this drug be bio-activated and work to stop the virus?

Herpes simplex infection can be treated using acyclovir. This is the first drug used to effectively treat viral infections. It is bio-activated by a viral kinase so it doesn't activate in normal healthy cells. Its ultimate end effect is premature chain termination of growing viral genome. Since the viral polymerase doesn't proofread, it won't remove acyclovir from the growing chain ending polymerization. (Side note: Virus-infected cells make DNA much more rapidly and and use viral polymerases that are much simpler that host polymerases)

How would high concentrations of H+ and CO2 shift the O2 binding curve? What are the "Effect" names used to describe blood buffering of CO2 and H+? What would the pkas of side chains for the T and R forms be relative to each other?

High H+ and CO2 would shift O2 binding curve to the right resulting in more release of O2 into tissues (induces T conformation). Blood buffering of CO2 is described as the Haldane Effect. Blood buffering of H+ is described as the Bohr Effect. Side chains in the T-form would have slightly higher pIs than in the R-form to promote attraction of H+ ions. (T-form usually in acidic environments while R-form usually in basic environments)

How can oral solutions of glucose help in simulating electrolytic uptake in the intestines?

High glucose and sodium in lumen (apical side) of intestine will promote uptake of glucose and sodium by SGLT2 (symport -- 2nd active transport) into endothelial cell. Glucose will exit out of GLUT2 into blood (basolateral side). Na+ is pumped out by Na/K-ATPase. High [Na+] on basolateral side leads to pericellular transport H20 and Cl- (between junctions of two endothelial cells). Overall, drinking a sports drink rich in sugar and sodium will lead to faster hydration in blood since more water is being sucked into the blood by increased sodium and glucose. Side note: KCl and sodium citrate used to treat dehydration from cholera. b

What is the difference between a holoprotein and an apoprotein?

Holoprotein: fully-functional protein with all required prosthetic groups Apoprotein - protein with prosthetic groups removed

How will the response change if receptor number were decreased for hormones with excess receptors and hormones without?

Hormones with Excess Receptors - a decrease in receptor number increases the hormone levels needed for a specific response, but not maximum response (right shift in curve) Hormones without Excess Receptors, increases hormone levels needed and also decreases maximum response

How do humans adapt to hypoxic conditions such as high altitude changes or emphysema?

Humans adapt by increasing red blood cell 2,3-BPG. This results in the O2 binding curve shifting to the right which lowers Hb saturation in lungs and tissues, but the net result is release of normal amounts of O2 to the tissue.

How do hydrophilic and lipophilic hormones differ in transport through the blood, metabolism, and excretion?

Hydrophilic hormones: Blood Stream: Flow freely flow through blood solution, bind to receptors on the cell membrane (can't get into cells) and use signal transduction (second messengers and enzyme-linked receptors) Metabolism: break down A-A bonds Lipophilic Hormones: Blood stream: Only free hormones that are biologically active when in bloodstream; protein-bound hormone acts as a buffer and slows rate of metabolism of H. Receptors of these hormones usually in nucleus in cell (can enter cell). Thus, they can serve as transcription factors (activate HRE). Metabolism: inactivation of active side groups, conjugation of charged groups that increase solubility Rate of removal proportional hormone concentration (1st order). Excretion takes place in urine.

Out of the four non-covalent forces used in folding of the tertiary protein structure, which one is the most important?

Hydrophobic Interactions (out of H-bonding, ion-ion attractions, and ion-dipole) This interaction has a big net stabilizing effect when it comes to protein folding.

What is the connection between the hypothalamus and the anterior pituitary gland?

Hypophysial Portal System: connection between two is vascular, not neural. Goes from arteries, to capillaries (hypothalamus), to veins, to capillaries (ant. pit.), to veins.

What does the QRS Complex represent in ECG?

QRS complex represents depolarization of the ventricles.

What tests are used to monitor functionality of the extrinsic and intrinsic pathways?

INR (also referred to as PT test) and PTT test respectively. Both of the most common forms of hemophilia will result in abnormal PTT test (intrinsic).

What is a drug that reversibly binds to Cox enzymes to reduce side effect involved with aspirin.

Ibuprofen -- competitive inhibitor

Why can't polar molecules freely diffuse through the membrane in terms of entropy S?

If Sm represented entropy of polar molecule inside membrane and S1 and S2 represented entropy from down a conc. gradient, Sm >> S1 or S2. Thus, a transport protein is needed for transport across a membrane.

How do reversible inhibitors affect Vmax and Km?

If competitive inhibition, then Km would decrease while Vmax increases. If non-competitive or uncompetitive inhibition, then Vmax will decrease while Km will remain the same or increase respectively.

Why is If, or "funny" current, so important in pacemaker cells?

If current is important in regulating heart rate and the speed of diastolic depolarization. If current, also called pacemaker current, will generate a net inward current by moving Na+ in and K+ out.

How do pacemaker cells pace the heart?

In a pacemaker cell, there is no real resting membrane potential since the cell is constant pacing by itself. Thus, since this cell automatically brings membrane potential toward threshold for next firing of AP, it does not require an external stimulus.

How is anticoagulation initiated?

In addition to the pro-coagulatory effects of thrombin, it also binds to a membrane receptor (thrombomodulin) which initiates part of anticoagulation. This initiation usually results when thrombocyte concentration is very high.

In nerve membranes, what ion uses double-gated channels? Why does it use this?

In nerve membranes, sodium can use double-gated channels. In a quick response to depolarization, "a-gates" open ("activate") while "i-gates" are still open. In a delayed response, "i-gates close" inactivating influx. During repolarization, "a-gates" open and "i-gates" re-open Potassium channels in nerve membrane have a single-gated channel that activates in a delayed response to depolarization. "A-gates" close as original stimulus (depolarization) disappears or at start of repolarization

The G-protein activation-inactivation cycle consists of GDP or GTP bound to an alpha, beta, and gamma subunit. What combination of units and GDP/GTP is inactive? Which is active?

Inactive - GDP bound to alpha, beta, and gamma subunits Active - GTP bound to alpha unit (once alpha unit produces its effect, GTP is hydrolyzed to GDP allowing alpha subunit to recombine with beta and gamma)

What are two different ways DNA can be targeted in cancer cells that rapidly undergo DNA synthesis?

Inhibition of thymidylate synthase - this enzyme involves a thiol group acting as a nucleophile to transiently add to the pyrimidine. However, fluoridation of the pyrimidine ring prevents separation of the enzyme and substrate leaving an alkylated enzyme active site and a dead enzyme (irreversible). Fluoro-uracil must be bio-activated by addition to ribose-5-phophate using normal metabolic enzymes. Inhibition of dihyrofolate reductase - competitive inhibition of both reactions 2 and 3 (see figure) by methotrexate

What is the QT interval in ECG?

QT interval is the time from the start of ventricular polarization to the end of ventricular repolarization.

What are integrins?

Integrins are transmembrane receptors that link cytoskeleton to ECM. Some can bind to one component of ECM while others can bind to multiple. Overall, integrin is the link between the ECM and the cytoskeleton of the cell providing a strong anchor. Weak binding with integrins, but multiple can be strong. This allows adaptability with cell (wants to detach to move or stay for growth)

Why can depolarization only be created by inward current?

Inward current of sodium and calcium ions will lead into depolarization while outward current of potassium ions leads to repolarization. Thus, outward current will always be repolarizing since this makes membrane potential more negative.

Are serpins reversible or irreversible inhibitors?

Irreversible

What are isometric, isotonic, concentric, and eccentric muscle actions?

Isometric action - muscle tension or force as a function of different fixed external muscle lengths (Length-Tension Relationship) Isotonic action - results from muscles changing length as a result of the force of contraction. (two types are concentric and eccentric) Concentric action - action that occurs when the muscle shortens to move load (if muscle force is greater than attached load) Eccentric action - action that occurs when muscles develop tension while lengthening or being stretched while active (muscles can function as shock absorbers, springs, motors)

What are isozymes and how do they affect enzyme activity?

Isozymes are enzymes that catalyze the same reaction, but are different in structure, kinetics, and are coded by different genes. Isozymes such as hexokinase and glucokinase both catalyze the same reaction, but glucokinase is only found in liver and is only active with high glucose concentrations.

What is an afterdepolarization?

It is a large amplitude depolarization caused by reactivation of Ca2+ channels that had previously undergone their activation/inactivation cycles. This can lead to arrhythmias.

What is the significance of the absolute refractory period (ARP)?

It is the time period in the AP where no further action potential can be elicited no matter how strong the stimulus is applied to the membrane.

What is the major contributor to the formation of phase 1 in the ventricular AP?

Ito -- transient potassium channel sensitive to Ca2+. Other channel that's active is ICa

What is Ohm's Law when applied to ionic currents through the membrane channels? What does conductance (G) mean?

Ix = Gx*NDFx = Gx*(Vm-Ex) Basically saying that current carried by ionic species X through membrane channels is proportional to the NDF for species X (Similar to Fick's equation for nonionic substances) Gx represents conductance. Gx is proportional to the total number of open channels selective for particle X. Thus, increased conductance increases ionic mobility across cell and current overall. Fractional Conductances: gNa = Gna/Gm where Gm is total conductance (add all conductance terms) Vr = gNa*ENa +Gk*Ek+gCa*Eca+gCl*ECl - GpIp

What is the equation for current density (related to flux density) for ion X?

Ix = zx*F*Jx Ix - current density Jx - flux density z*F = charge of ionic species (z=valence, F = Faraday's constant)

How is permeability represented using Fick's Law? (used when measuring concentration change across a membrane)

J = (-uRT/d)*(delta C) = P*(C2-C1) d = membrane thickness (proportional to temperature, membrane mobility, and thickness)

How will Km and Vmax change when an irreversible inhibitor is introduced?

Km will stay the same and Vmax will decrease.

Which part of the sarcoplasmic reticulum is responsible for releasing stored calcium?

Lateral cisternae (rather than the longitudinal tubes). More developed in Type 2 muscle.

What are the directions of the three Leads on Einthoven's Triangle?

Lead 1 - Left arm (+) to right arm (-) Lead 2 - Left leg (+) to left arm (-) Lead 3 - Left leg (+) to right arm (-)

What are lipid rafts and why might they form?

Lipid rafts are subdomains of the plasma membrane that contain high concentrations of cholesterol and glycerophospholipids. Presence of specific proteins like caveolin can lead to formation of lipid rafts and promote formation of pits for endocytosis. Length of trans-membrane helices can influence nature of lipids to provide hydrophobic match.

How does lipophilic secretion differ from hydrophilic secretion of messengers?

Lipophilic secretion is diffuses through the cell membrane while hydrophilic secretion is done through exocytosis. Calcium ions trigger exocytosis.

Categorize the following hormones by lipophilic or hydrophilic.

Lipophilic: Steroid hormones, thyroid hormones, vitamin D Hydrophilic: Protein/Polypeptide hormones and catecholamines

How does receptor-mediated endocytosis operate as a transport mechanism?

Lipoproteins particles are taken up by specific cell types. Receptors migrate to caveolin-containing pits: membrane areas with large negative curves. LDL, HDL, and Chylomicrons are taken up by this process.

What are the two amino acids that are post-translationally modified in collagen? What are the enzymes that catalyzes this modification?

Lys and Pro to HydroxyLys and HydroxyPro. Lysyl and prolyl hydroxylase enzymes are used in the ER for this modification. Hydroxylases require Fe and ascorbic acid (Vitamin C). Sugars added vis glycosyltransferases.

What are MMPs? What is an inhibitor for MMPs? What are some other inhibitors that help regulate ECM destruction?

MMP - Matrix Metalloproteases These enzymes are critical for remodeling. They are Zn-dependent proteases that are specific for hydrolysis of protein components of the ECM (eg. collagenase-1, stomelysin-1). The inhibitors that regulate MMPs are TIMPs (Tissue Inhibitor MP). PAIs (Plaminogen activator inhibitors) inactivate plasminogen to plasmin which can lead to proteoylsis of ECM.

What is the mechanism of an ABC Transporter?

Mechanism involves two different conformations with substrate binding site oriented either to inside the cell or outside. Conformation change caused by substrate and ATP binding inside/outside and ATP hydrolysis outside/inside.

How does the membrane environment and cytoplasmic environment compare in terms of dielectric constant and viscosity?

Membrane environment: low dielectric constant, high viscosity, Cytoplasmic environment: high dielectric constant, low viscoisty Low dielectric of membrane makes strength of H-bond, salt bridge much greater, relative to aqueous

What is methotrexate used for?

Methotrexate is a competitive inhibitor of dihydrofolate reductase, an enzyme used in thymidine synthesis. It will ultimately deplete folate leading to stopped T synthesis and really all nucleotide synthesis.

What type of molecules are often the most potent competitive inhibitors (and can make excellent drugs)?

Molecules that mimic transition states of other substrates

Where are most of the coagulation factors synthesized? What factor is usually obtained through diet?

Most coagulation factors are synthesized in the liver. Calcium ions (Factor IV) are obtained through diet with help from Vitamin K.

What are some differences between a muscle action potential and an endplate potential?

Muscle AP - sequential change in conductance of Na+ and K+, shorter (3 msec), has refractory period, all-or-nothing, voltage dependent EPP AP - simultaneous change in conductance of Na+ and K+, longer (10 msec), no refractory period, local and graded, ACh dependent

How can penicillin be resisted by bacteria?

Mutant forms of the transpeptidase enzyme exist that do not exclude water from the active site. Beta-lactamase inhibitors are thus used along with penicillin to account for this.

What is Myasthenia gravis?

Myasthenia Gravis (MG) is a disease of the ACh receptors. Autoantibodies in the NMJ can bind to the receptors and block any interaction with ACh but they do not alter the esterase activity.

How are myocytes connected? With this connection, how can the heart function as a syncytum?

Myocytes ares connected to each other through intercalated disks. The disks contain gap junctions and are electrical synapses which permit impulses to be transferred from one cell to another through direct transfer of ions. Thus, the AP through a single cell can be propagated to its adjacent cells through gap junctions.

What is the difference between myogenic and neurogenic electrical activity?

Myogenic - action potentials initiated by cardiac myocytes themselves Neurogenic - action potentials initiated by local synaptic or end-plate potentials

Why does rigor mortis occurs upon death?

Myosin molecules are loaded with the energy of ATP at rest. When muscle is depleted of energy, the contractile system stop in the rigor complex because additional ATP is required for dissociation of the actin-myosin complex.

What is the charge of 2,3-BPG and the charge of the cleft between the beta-subunits in hemoglobin?

Negative and Positive respectively Cleft of beta-subunits contains lysine and histidine residues). These charges are not present in HbF (uses gamma subunits), so reduced binding to 2,3-BPG.

How does long distance communication differ between the endocrine and nervous systems?

Nervous system communication -- fast, local, specificity through wiring (projection of neurons) Endocrine system communication -- slow, diffuses in blood stream, specificity determined by receptors

What are the differences between muscarinic and nicotinic ACh receptors?

Nicotinic -- NMJ, ANS. ACh opens non-specific cationic channels. On post-ganglionic neurons. Muscarinic -- ANS,CNS- ACh acts via DAG/IP3; acts by increasing or decreasing enzyme activity. On effector cells.

Most neurotransmitters in nervous system are stored in secretory vesicles; however, which neurotransmitter diffuses across membranes and synthesized when needed for release?

Nitric oxide (NO)

What are the six atoms that lie in the "peptide group" plane?

Nitrogen and hydrogen in amide, two alpha carbons, one carbonyl carbon, and oxygen. Partial double bond between carbonyl and nitrogen keep this portion in a plane.

What are the two classes of lipids? What type of lipids follow under these two classes?

Non-polar lipids: triglycerides used for energy storage Polar lipids (amphipathic): phospholipids, sphingolipids, cholesterol (Cholesterol is precursor to steroid hormones and prostaglandins)

What are the normal total platelet counts per volume blood? What are the required counts for major or minor surgeries?

Normal -- >150,000/ul Major surgery -- >100,000ul Minor surgery -- >50,000ul

Differentiate between the locations O-linked and N-linked glycosylation takes place in cell.

O-linked - in Golgi most of time N-linked - in ER, but sometimes Golgi

What type of inhibitors are phosphonate esters that contain a F- as a leaving group?

Organophosphorus Poisons (eg. sarin, parathion). They inhibit acetylcholine esterase

What is the definition of osmotic pressure (pi)?

Osmotic pressure equals the pressure which must be applied to a solution compartment (contacting a pure water compartment through a semipermeable barrier) in order to prevent a net flux of water. Hydrostatic vs. Osmotic pressure in Blood Hydrostatic from pushing of blood on arterial surface, osmotic is "sucking pressure" on interstitial fluid to restore osmolarity.

What type of disease is Huntington's disease?

Poly-Q Disease Increased secretions of protein with dozens of repeated Gln residues leads to protein misfolding resistant to proteolysis. This process also inhibits proteosomes since they can bind to polyQ containing protein and not digest it. Thus, there is an inhibition of proteosomes and accumulation of misfolded proteins.

How is the hypothalamus and the posterior pituitary gland connected?

Post pituitary gland is an extension of hypothalamus. Nerves with cell bodies in specific areas of hypothalamus send axons down pituitary stalk to terminate on blood vessels in posterior pituitary. (Paraventricular and supraoptic nerve nucleus in hypothalamus)

What is post-tetanic facilitation?

Post-tetanic facilitation (PTF) results from an accumulation of a small amount of excess calcium in the terminal over what it had before the stimulation or exercise. Could be result of a deficient sodium-calcium exchanger. This can lead to depletion of ACh from loading vesicles and failure in a muscle action potential.

What is the relationship of pre-load and after-load to skeletal muscles?

Pre-load: After activation, muscle force builds up force equal to the load hanging on the muscle and stretches the series elastic elements (SE) components within the muscle. After-load - working muscle experiences additional resistance not directly related to the load

What are the steps involved in a noradrenergic transmission?

Pre-synaptic events: Depolarization caused by AP, opens voltage-gated sensitive Ca2+ channels, influx of Ca2+causes exocytosis. Post-synaptic events: Receptors (alpha 1 & 2, beta 1 & 2), depends on the receptor subtype present, but some of these receptors have opposite effects in some tissues. Removal mechanisms (re-uptake, metabolism) Re-uptake: NE can be reused or metabolized Metabolism: Monoamine oxidase (MAO): breaks down neurotransmitter in neuron.

What is the difference between primary and secondary control system problems with the hypothalamo-pituitary unit? What is the net result of each?

Primary: problem with target tissue leads to hormones going in different direction (due to loss of negative feedback) eg. hyperthyroidism Net Result: low TSH, high T3 and T4 (no response in tissue) Secondary: problem with anterior pituitary, but hormones continuing going in normal pathway (target tissue responding to hormone, but anterior pit. not responding, producing, etc.) eg. secondary hyperthyroidism Net Result: high TSH, high T3 and T4 (no feedback control)

What is the name of the enzyme that removes the N- and C-terminal globular domains from procollagen triple helix to induce aggregation outside the cell?

Procollagen peptidase

What are the different roles played out by proximal histidine and distal histidine in hemogobin?

Proximal histidine: Promotes conformational change between T and R. When O2 binds to iron, iron moves into heme plane which causes movement of proximal His. Movement of this histidine when O2 binds causes the F helix in hemoglobin to move which cause T to R conformation change (tertiary structure change) Distal histidine: stabilizes oxy-form of heme by H-bonding to the O2; also helps prevent oxidation of iron ion and protects against endogenous CO

For mild and moderate hemophiliacs, what two types of proteins of the missing factor are used if necessary (during trauma)?

Purified and recombinant proteins

Carrier-mediated transport is highly temperature dependent. What is the equation used to calculate the fold-change in flux for every 10 degree (K) change in temperature?

Q10 = flux at T (K)/flux at (T-10) (K)

How do reversible and irreversible inhibition differ from one another?

Reversible - Interaction between inhibiting molecule and the enzyme cannot convert substrate into product. Enzyme recovers its normal activity once inhibitor diffuses off. Irreversible - Enzyme reacts with the inhibitor to form covalent bond that does not break in anything resembling real time. Both the enzyme and the inhibitor will ultimately be destroyed through course of inhibition ("suicide substrates")

What are some disorders associated with right-axis deviation (>+105 degrees) and left-axis deviation (<-30 degrees) of the mean cardiac vector?

Right-axis Deviation - Pulmonary Hypertension, other pulmonary conditions Left-axis Deviation - Hypertension, Hypertrophy

What causes hyperkalemia?

Rise in extracellular K+ concentrations causes a decrease in Ek and will thus depolarize the cell. This can lead to cardiac excitability and/or arrhythmias (uncoordinated heart rhythms).

What is the difference between a screening and a diagnostic test?

Screening tests can not be used to provide a specific diagnosis. A diagnostic test can narrow down the possibilities to one.

What are the three amino acids that form the Catalytic Triad in serine proteases?

Serine, Histidine, and Aspartate

What is the structure of Type 4 Collagen?

Similar to type 1 collagen, except it retains its N- and C-terminal domains when it forms aggregates. Protomers of Type 4 collagen interact to form dimers (at NC1 domain) and 4 dimers together can form a tetramer (interact at 7s domain). Multiple tetramers interact to form suprastructure of Type 4 collagen (network more than fiber)

Why are red blood cells indented in the middle?

Since red blood cells must maintain high fluidity to squeeze through capillaries, they have an indentation in the cell to increase fluidity.

What are the typical concentrations for sodium and potassium intracellularly and in the extracellular fluid?

Sodium: Intracellular: ~10 mmol Extracellular: ~140 mmol Potassium Intracellular: ~140mmol . Extracellular: ~5 mmol

How is the "soft" clot of fibrin converted to a fibrin network, or a "hard". What amino acid residues are involved?

Soft clot is converted to hard clot by fibrin cross-linking which requires Factor XIIIa for catalysis. This makes an isopeptide bonds between fibrin monomers that greatly increases strength of fibrin (not just non-covalent bonds). The amino acids involved in amide crosslink are lysine and glutamine.

What are the differences between the somatic and autonomic nervous systems?

Somatic -- voluntary, all-or-none response, excitatory only, required for activity, no inter-ganglion ANS -- involuntary, graded response, excitatory or inhibitory, modulate ongoing activity, has a ganglion

What causes spur-cell anemia?

Spur-cell anemia results from increased conc. of cholesterol in erythrocyte plasma membrane, resulting in less fluid membranes that are prone to rupture. Liver disease impairs the liver's ability to esterify cholesterol, which leads to secretion of lipoproteins with high levels of free (non-esterified) cholesterol. Non-esterified cholesterol freely moves from serum lipoproteins to the out leaflet of erythrocyte plasma membrane. Results in more rigid erythrocyte plasma membrane. Decreased fluidity of spur cells prevent them from easily passing through capillaries and increases shear force between RBC and capillary wall. Increased shear force damages these cells and are destroyed by macrophages in spleen leading to anemia.

How do the sympathetic and parasympathetic nervous systems differ from one another?

Sympathetic: cell bodies are in thoracic and lumbar spinal cord, ganglia mostly in paravertebral but some unpaired ganglia plexus in abdomen (prevertebral), sensory afferents are nociceptive (pain) Parasympathetic: cell bodies are in brain stem or sacral spinal cord, ganglia close, or in, tissue innervated, sensory afferents are physiological (vagus - all viscera in thorax and abdomen)

What does the T wave represent in ECG?

T wave represents repolarization of the ventricles.

Why can TTX only partially work in for slowing down SA AP?

TTX blocks Na+ channels, but since depolarization of SA node is mainly caused by calcium current, role of sodium current is less and consequently contributes less to depolarization.

What is the endplate potential (EPP)?

The endplate potential is a non-propagated membrane depolarization that results in response to the transmitter (ACh) released. ACh is a ligand for the ion channels Na+ and K+ in the muscle membrane. Permeability or conductance change in this area from ACh binding increases conductances of Na+ and K+ resulting in local currents in the post-synaptic (endplate) membrane. These depolarizing currents are normally sufficient to generate a muscle AP.

What is the safety factor and why is it clinically important in the NMJ?

The extra number of ACh vesicles released during a nerve action potential represents the "Safety Factor". It releases 50 ACh vesicles (quanta), more than enough to generate a muscle action potential.

What are the steps involved with fibrinolysis in blood coagulation? What proteins are involved?

The protein C/protein S complex activates the serine protease activity for protein C and binds to endothelial cells to activate tPA (tissue plasminogen activator) inside the cell. tPA exits the cell to activate plasminogen to plasmin. Plasmin initiates the proteolytic cleavage of the fibrin protein into small fragments.

What does it mean for a sodium pump to be electrogenic?

The sodium pump exchanges charge asymmetrically (3:2 exchange) and is considered electrogenic in contrast to electroneutral transport.

What causes the symptoms experienced with cystic fibrosis (CF)? What is the mechanism behind CF?

There is a mutation in the gene for CF transmembrane conductance regulator (CFTR) protein. CFTR is a ligand channel that transports chlorine ions and is found in exocrine glands in lungs, liver, pancreas, and intestines. A deletion of phenylalanine from the protein causes mis-folds in ER targeting it for proteolysis so it never gets to plasma membrane. Loss of CFTR activity causes low [NaCl] in secretions so less water is secreted to balance osmotic pressure. Therefore, there is less water in secretory ducts to solvate proteins, mucus, etc. causing thickened secretions in lungs, pancreas, and bile ducts that are difficult to clear, so mucus accumulates. Accumulated mucus in lungs causes increased susceptibility to infections and accumulated mucus blocks pancreatic ducts impairing secretion of pancreatic enzymes. This causes poor growth and inflammation that can lead to diabetes. Blocked bile ducts impairs absorption of lipids and fat-soluble vitamins, causing diarrhea and deficiency of vitamins A, D, E, and K.

What mechanisms are used for ligand-gated channels when functioning in signal transduction?

These channels usually have 5 subunits which form a central pore in membrane. These channels are selective to charge and can be selective to a certain ion (eg. Na+ only). These channels are either opened or closed and can change conformation if one or more subunits bind a messenger. Once messenger diffuses away or metabolized, the channel closes.

How do integrase inhibitors work (such as suppressing HIV Integrase activity)?

These inhibitors all bind to the strand transferase active site by interacting with the Mg2+ molecules. Some other methods of inhibition are being studied since we know integrase can identify human DNA sequences through interaction with a host protein, LEDGF/P75.

How are some serine proteases activated? Why is this critical?

These proteases, which are zymogens at first, are activated by proteolysis (irreversible post-translational modification). Activation must be controlled so enzymes digest material at the correct time and place.

What is the role of the protein C and protein S complex?

This complex activates the serine protease activity of protein C targeting Factors Va and VIIIa, both factors involved with the scaffold and amplifying thrombin activation.

What is the process of bio-activation?

This is a process where an uncharged precursor can be converted into a charged molecule in vivo. This can be important for clinical enzyme inhibitors since precursors must first be uncharged before it enters its target tissue. Then, it would become "activated" with a charge to carry out enzyme inhibition.

How is the activation of thrombin amplified by thrombin itself?

Thrombin can activate factors VIII and V by proteolysis as well as additional factors VII and X11, both of which eventually lead to more thrombin production (positive feedback). In addition, Factors VIIIa and Va serve as scaffolds to enhance activity of Factors X and prothrombin, respectively. These scaffolds would place Factors IXa and Xa (proteases) adjacent to binding sites for the substrate factors, increasing likelihood of activation. With Factor Va, the reaction is 10,000 times faster.

How does thrombin convert fibrinogen (soluble form) to fibrin (insoluble form)?

Thrombin would remove the N-terminal tails of fibrinogen proteins contain multiple negative charges (polar). Once the negative charges were removed, the fibrin molecules can self-assembly into a polymer meshwork that is insoluble.

What are post-translational modifications always catalyzed?

To allow regulation. Can be reversible or irreversible such as phosphorylation of serine in proteases vs. hydroxyProline respectively.

What is the difference between tonic receptors and phasic receptors

Tonic (slowly adapting) receptors - provide a spike train as long as the stimulus persists. Stepwise stimulus would respond with an immediate increase in frequency followed by slow decline to a lower level. Phasic (fast adapting) receptors - one brief burst of impulses when stimulus is applied; becomes silent during prolonged stimulus

What is the difference between twitch, summation, and recruitment mechanical responses of skeletal muscles?

Twitch - the response to a single action potential is a sharp rise and fall in force. Summation - increased force production by a muscle due to repetitive stimulation (isometric contraction) Recruitment - increasing the number of active motor units increases the number of muscle fibers participating so larger mechanical response. Greater contraction with more active muscle fibers. Overall: Force = f(AP frequency, # of motor units)

What are the primary differences between Type 1 and Type 2 fibers in muscle tissue?

Type 1 fibers - slow twitch, oxidative fibers Type 2 fibers - fast twitch fibers (Type 2a - fast twitch oxidative, Type 2b - fast twitch, glycolytic fibers)

How do Type 1 and Type 2 muscle fibers differ in metabolizing energy?

Type 1 fibers: slow contracting, primarily aerobic pathways, low power work and high endurance with oxygen Type 2 fibers: fact contracting, Type 2a more aerobic with same myosin ATPase in Type 2b fibers which are anaerobic, high power capacity, but fewer contractions due to limited energy storages and lactic acid production

What amino acid is a derivative for norepinephrine and epinephrine production?

Tyrosine

Why is the T-wave positive in ECG since it represents repolarization instead of depolarization?

Ultimately, this is due to the longer action potential duration in endocardial myocytes than in epicardial myocytes, caused by different K+ channel expressions. So repolarization will actually being in the epicardium and transmit towards the endocardium. Repolarization would be moving away from the positive electrode resulting, which is equivalent to depolarization moving toward the positive electrode.

What is UPR stand for?

Unfolded Protein Response - build-up of aggregated or mis-folded protein in the ER may trigger the UPR to ultimately cause cell death

What are the functions of Von Willebrand factor in platelet aggregation?

Upon unfolding, the vWF proteins bind to collagen and to platelet membranes facilitating both platelet adhesion and particularly aggregation. Also, vWF binds to stabilize Factor VIII in circulation. Insufficiency of vWF or mutations in the FVIII-binding domain lead to insufficiency ins that Factor. This leads to a bleeding disorder.

How is elastin crosslinked?

Uses lysyl oxidase andto convert amines to aldehydes on 4 Lys residues. These residues can then make a desmosine crosslink, unique crosslink of elastin. Crosslinking will prevent complete dissociation of protein chains when fibers are stretched. While in amorphous association (relaxed), hydrophobic interactions persist which allows flexibility of elastin polypeptide chains.

What is v0, and how is it measured?

V0 is the initial velocity of the enzyme-catalyzed reaction. It is found by measuring the initial rate of product production for that enzyme.

What is Van't Hoff's law? What does it measure? What happens to equation if multiple solute species are used?

Van't Hoff's Equation: pi = CRT pi = osmotic pressure C = concentration T = absolute temperature Multiple solutes with individual concentrations used: pi = (C1+C2+C3+...)RT (colligative property) Change in osmotic pressure would be same equation, just using change in concentration as well.

What is the name of the attachment protein that has been identified at each of the intercalated disks aiding in transmitting force from one cell to the next?

Vinculin

Why are multiple-drug cocktails used to treat HIV infections?

Viral reverse transcriptase is both promiscuous and error-prone with mutations that occur rapidly. Some of these mutations will prevent the binding of anti-viral drugs to the RT enzyme by affecting the binding pocket. This causes the drug to lose effectiveness, so multiple drugs must be used and switched out every so ofter because of viral resistance.

How can vitamin K activity be reduced in hypercoagulability? What drug can be used to inhibit vitamin K?

Vitamin K reductase enzyme can be competitively inhibited which decreases amount of active vitamin K. Usually, small amounts of inhibitor is used to only reduce hypersensitivity of enzyme and not coagulation altogether. Warfarin is a drug that can competitively inhibit vitamin K reductase.

What is the equation for membrane potential? What side of the membrane is more negative than the other?

Vm = (inside electric potential) - (outside electrical potential) ICF is is typically more negative at resting membrane potential.

What are Vmax and Km? How are they determined from a v0 vs [S] plot or a double-reciprocal plot?

Vmax is the maximum velocity and enzyme can catalyze a reaction. The Km is the substrate concentrations at half the Vmax.

What are some differences between weakness and fatigue at the neuromuscular junction?

Weakness results from: 1. lack of action potentials in the nerve (tick venom, local anesthetics) 2. NMJ failure (Botox, curare, MG, pesticides) 3. inability to generate MAPs or their spread in muscle. Fatigue is time dependent weakness. Myasthenia gravis disease results in weakness and fatigue due to marginal NMJs that fail with repeated use and non-functional NMJs.

What type of amino acids polymerize to form peptide bonds?

alpha-amino acids GABA and beta-alanine are other amino acids that are not alpha