Biochemistry Exam III
What percentage of cholesterol is esterified in the body
10-15%
Ferroportin
What iron channel protein does free (ferrous) iron (mobilferrin) pass through to enter circulation?
acute hepatic porphyrias
(ALA) and (PBG) accumulate
Indirect effects of GH
(via IGF): a) Increased Protein synthesis (Growth)
abetalipoproteinemia
*absence of MTP* ; Low B-48, low B-10 patients with this disease cannot absorb fat
B12 and Folate deficiency
- B12 and folate deficiency can be caused by malabsorption of the GI tract. - B12 deficiency is rare except in strict vegetarians. Large amount of B12 is stored in liver. Symptoms of deficiency only shows up after long-standing malabsorption. - B12 deficiency can be due to *the lack of intrinsic factor* essential for the absorption in gut after stomach surgery or autoimmune response against intrinsic factor. Direct injection of B12 should be given to patient. - Vitamin B12 and folate are measured in plasma by immunoassay. - Absorption of vitamin B12 can be used as a test of terminal ileal function. - Deficiency in B12 and folate shows neurological manifestations - demyelination, peripheral neuropathy, subacute combined degeneration of the spinal cord, dementia and optic atrophy. - Supplement of vitamin B12 to elderly patient shows improvement in memory loss in patients with Alzheimer's diseases - Giving folate alone to patients with vitamin B12 deficiency risks precipitating or exacerbating the neurological manifestations of B12 deficiency.
FGF-23
- Fibroblast growth factor 23 - accumulates during renal failure - the kidneys are responsible for getting rid of phosphorus, but they cannot cope when there is too much of it. The gut keep absorbing phosphorus even though the kidneys can't keep up - as a result of [phosphorus] going up, [Ca2+] goes down, thereby stimulating the parathyroid gland to secrete PTH to increase [Ca2+] ⇒*2° Hyperparathyroidism* ⇒ Bone disease - Inhibits 1-α-Hydroxylase
FA elongation
- The elongation of FA takes place in ER, and is similar to FA synthesis. The enzyme complex is called *FA elongase* - Malonyl CoA serves as the donor of 2 carbon unit - CoA, rather than ACP is used for binding the intermediates - Very long FA (22-24 carbons) are formed mostly in the brain
Arachidonic acid gives rise to which 3 major groups of eiconasoids?
1) Prostanoids via Cyclo-oxygenase 2) Leukotrienes via Lipoxygenase 3) Epoxides via Cytochrome P450
Characteristic features of biologically active prostaglandins
1. A 20-carbon fatty acid 2. A 5-membered ring (carbons 8-12) 3. A *trans bond* between *carbons 13 and 14* 4. An α-oriented OH group at carbon 15 5. Differences in the main PG groups are in the cyclopentane ring substitutions (X,Y)
chylomicron metabolism
1. Intestinal mucosal cells secrete nascent TG-rich chylomicrons produced primarily from dietary lipids 2. Apo C-II and apo E are transferred from HDL to nascent chylomicrons 3. Extracellular *lipoprotein lipase*, activated by apo C-II, degrades TG in chylomicrons 4. Apo C-II is returned to HDL 5. Chylomicron remnants bind to specific receptors on the liver where they are endocytosed via apo E
VLDL and LDL metabolism
1. Liver secretes nascent TG-rich very-low-density lipoprotein particles 2. Apo C-II and apo E are transferred from HDL to nascent VLDL 3. Extracellular lipoprotein lipase, activated by apo C-II, degrades TG in VLDL 4. Apo C-II and apo E are returned to HDL 5. LDL binds to specific receptors on extrahepatic tissues and on the liver, where they are endocytosed.
Steps in Lipid Digestion and Absorption
1. Minor digestion of TG (short chain) in mouth and stomach by lingual and gastric lipases. Important in neonates for digestion of milk fat (pre-emulsified, short chain TG) 2. Mechanical emulsificationin stomach 3. Duodenum/jejunum: emulsification by bile salts; Hydrolysis of all lipid esters by *pancreatic lipases* 4. *Mixed micelle* formation with bile salts and lipolytic products 5. Passive absorption of lipolytic products from the micelle by epithelial cells 6. Re-esterification of lipolytic products to TG, PL, and CE 7. Assembly of chylomicrons with apoproteinB-48 8. Transport of chylomicrons by *lymph*
Catecholamine secretion
1. Stress-induced impulses from adrenergic nuclei in hypothalamus 2. Release of Ach from preganglionic neurons innervating adrenal cells. 3. Ach depolarizes adrenal cells, Ca++ enters 4. Ca++triggers exocytosis of chromaffin granules loaded with catecholamines. 5. Release into extracellular space.
LDL receptor pathway
1. The receptor is located in clathrin-coated pits 2. LDL-receptor complex is taken up by endocytosis 3. Clathrin coat is lost, and the vesicle fuses with endosome 4. The pH of the endosome is decreased, resulting in dissociation of LDL and the receptor 5. Receptor is recycled 6. LDL remnant is transferred to lysosome, where degradation of protein and lipids takes place 7. The released cholesterol is used for synthesis of membranes, bile acids or steroid hormones 8. Excess cholesterol suppresses synthesis of LDL receptors as well as cholesterol 9. Oversupply of cholesterol is esterified by ACAT for storage as cholesterol ester.
AKT effects on cancer metabolism
1. Translocation of glucose transporters to the membrane 2. Activation of 2 glycolytic enzymes 3. Stimulation of Lipid (L) synthesis
Vioxx and cardiovascular effects
1. Reduced whole body PGI2 without changing TXA2levels (increased blood clots) 2. Vioxx-specific effects (not other COX-2 inhibitors)-cardio toxicity due to maleic anhydride metabolite 3. Effects appeared in long term (>18 months) but not in short term studies 4. Other COX-2 inhibitors have also been shown to have some adverse effects (only Celebrex is presently approved)
Palmitoyl-CoA
1st substrate in the biosynthesis of sphingomyelin
Serine is formed from...
3-phosphoglycerate The first step is oxidation (NAD → NADH) of 3 phosphoglycerate followed by transamination and dephosphorylation.
For what BMI categories should you suggest *pharmacotherpay* for weight management?
30+ (27+ w/comorbidity)
For what BMI categories should you suggest *surgery* for weight management?
40+ (35+ w/comorbidity
What percent of the diet is do dietary lipids provide?
>35% of calories
Phospholipids
A class of lipid molecules in which a phosphate group is linked to glycerol and two fatty acetyl groups; a chief component of biological membranes
Fatty acyl synthase
A dimer, arranged in a head-to-tail configuration Each monomer contains all 7 enzyme activities, ACP, and a 4' phospho-pantetheine In prokaryotes the enzymes are separate proteins.
Aceruloplasminemia
A genetic disorder in which there is absence of the protein ceruloplasmin from blood and accumulation of iron in the pancreas, liver and brain, causing diabetes and progressive neurodegeneration with the tremors and gait abnormalities characteristic of Parkinson disease
Cystinosis
A lysosomal storage disease with excess cystine crystals build-up
Familial Hypercholesterolemia
A metabolic disorder that is caused by defective or absent receptors for LDLs on cell surfaces, that is marked by an increase in blood plasma LDLs and by an accumulation of LDLs in the body resulting in an increased risk of heart attack and coronary heart disease, and that is inherited as an autosomal dominant trait.
N-Acetylglutamate synthetase deficiency
A newborn infant was found to have hyperammonemia with respiratory alkalosis. An inherited defect in the urea cycle was suspected. Plasma citrulline levels were found to be low. Urinary orotate concentration was found to be normal. Extracts of a liver biopsy were assayed for N-acetylglutamate synthase. No activity was found. The cause of hyperammonemia in the baby is due to N-acetylglutamate synthase deficiency. Since citrulline is low, this indicates a defect in the urea cycle rather than transient hyperammonemia. It also rules out the involvement or defect of specific urea cycle enzymes. Urinary orotic acid concentration is normal so this also rules out the deficiency of carbamoyl phosphate synthase 1 (CPSI) and other subsequent enzymes of the cycle. The defects of urea cycle enzymes usually lead to higher orotic acid concentration. There is no cure. The treatment may involve injections of structurally similar compound, N-carbamoyl-L-glutamate, an analog of N-acetylglutamate. This analog likewise activates CPSI and mitigates the intensity of the disorder. However, the infant will still have severe mental retardation and brain damage. Sodium benzoate and phenylbutyrate are given to treat hyperammonemia.
Therapeutic window
A range of dosages between the minimal effective dose (MED) and the minimal toxic dose (MTD); its an alternative safety index of drugs
sphingosine
A single "tail", a C-C double bond, and an amino group used in forming amide linkages. Various sphingolipids are derived from this, such as ceramide. Derived from palmitoyl-CoA and serine.
sphingolipids
A sphingolipid with an R group consisting of a hydrogen atom only is a ceramide. Other common R groups include phosphocholine, yielding a sphingomyelin, and various sugar monomers or dimers, yielding cerebrosides and globosides, respectively. Cerebrosides and globosides are collectively known as glycosphingolipids.
Release of Arachidonic Acid from Membrane Phospholipids
A stimulus (can be cytokines, histamine, etc) binds to a cell that activates a membrane enzyme called phospholipase A2. The stimulus, for example, might be a condition that causes, or threatens to cause, tissue damage. Phospholipases act on phospholipids. In this case, the phospholipase A2 acts on a membrane phospholipid that contains arachidonic acid is a polyunsaturated fatty acid. The arachidonic acid released from the phospholipid is now the substrate for one of two enzymes. The first enzyme is cyclooxygenase (COX). The product of this reaction then proceeds through a further sequence of enzymatic reactions to produce a regulatory molecule that is either a prostaglandin or a thromboxane. The second possibility is for lipoxygenase (LOX) to act on the arachidonic acid. In this pathway, the actions of further enzymes lead to regulatory molecules in the family of the leukotrienes. All of the eicosanoid regulatory molecules tend to act locally as paracrines. This is because they are degraded too rapidly to move about the body through the circulatory system.
anti-thrombin III
A substance that inactivates ('turns off") thrre major activating factors of the clotting cascade: activated factor II (thrombin), activated factor X, and activated factor IX
N-acetyl-P benzoquinoimine
A toxic intermediate of acetaminophen detox and can lead to liver damage
Leukotrienes
A type of eicosanoid (arachidonic acid derivative) most important in asthma.
Mechanism of Aspirin
A widely used class of drugs, the non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, indomethacin, naproxen, and phenylbutazone all act upon the cyclooxygenase activity, inhibiting both COX-1 and COX-2. Aspirin is unique among the class of NSAIDs in that its actions on relief from pain (analgesia) and as an anti-inflammatory as well as a heart protective drug are not solely due to its ability to inhibit COX activity Aspirin transfers an acetyl group to the active site serine and irreversibly inactivates the enzyme
ALA dehydratase
ALA dehydratase is a -SH containing enzyme. It is very susceptible to inhibition by heavy metals, especially *lead* ALA can lead to neurological defects
When _______ levels are high (_______ levels low) the phosphorylation of HMG CoA reductase is increased. Thus cholesterol synthesis is inhibited when ATP levels are low.
AMP, ATP AMP is an activator of reductase kinase (the enzyme that phosphorylates HMG CoA reductase)
Akt
Activation of ______ leads to an increase in protein synthesis and cell growth AND also to the inhibition of apoptosis
What is the second most common porphyria?
Acute intermittent porphyria PBG deaminase deficiency PBG and 5-ALA accumulate in the plasma and the urine Symptoms: Localized abdominal pain, Urinary symptoms, Peripheral neuropathy
ACP
Acyl carrier protein
Glutamine synthetase is modulated by an enzyme cascade that involves ______________ and ______________
Adenylation and Uridylation
In non-hepatic tissues, amino acids are converted to __________ via transaminase reaction utilizing pyruvate as a substrate. It is then is transported to liver.
Alanine
What is the major amino acid substrate for gluconeogenesis?
Alanine
ALT =
Alanine AminoTransaminase Alanine is converted to pyruvate through a transamination reaction which transfers the amino group to a-ketoglutarate to form glutamate and pyruvate in liver. Pyruvate is utilized as energy source for ATP production or for gluconeogenesis.
What are the 2 circulation amino acids in the blood?
Alanine and Glutamine
For what BMI categories should you suggest *conservative therapy* for weight management?
All categories
Linoleic Acid
An essential fatty acid found in vegetables and nut oils; also known as omega-6 fatty acid. *essential*
Asparagine and Glutamine synthesis
Asparagine and glutamine are formed by direct amination with asparagine synthetase and glutamine synthetase using ammonia and ATP
Macroblastic Anemia is due to...
B12 defficiency causing a folate methyl trap and preventing the synthesis of dTMP. Therefore RBCs can't proliferate
Urea Cycle Disorders
Babies and patients with these disorders are unable to remove nitrogen from their bloodstreams. These patients have high levels of toxic ammonia in their blood and need immediate help. These patients usually are treated by a metabolic specialist or a biochemical geneticist.
Proteosome
Barrel-shaped protein complex that degrades damaged or ubiquitin-tagged proteins. Defects in the ubiquitin-proteosome system have been implicated in some cases of parkinson disease.
Which one, beans or wheat, is high in lys but low in methionine?
Beans Wheat is the opposite
What does the BUN test indicate?
Blood ammonia levels
Carbamoyl Phosphate Synthetase I
CPSI catalyzes the condensation and activation NH3 and HCO3- to form carbomyl phosphate (first nitrogen containing substrate). Uses 2 ATPs.The carbon that ends up in urea is originated from CO2 CPSI is allosterically activated by N-acetylglutamate.
Cortisol Secretion
CRH (hypothalamus) -> ACTH (anterior pituitary) -> cortisol (adrenal cortex) release
Vermapil
Ca2+ blocker used for BP control Best to administer before sleep so that you can match it up with high BP in the morning
Phentermine
Central acting only approved for short term use (3 months) cheapest weight loss medicine
acute lymphoblastic leukemia
Certain acute lymphoblastic leukemia(ALL) Require L-asparagine (a non-essential aa) Cause: defect in L-asnsynthesis Therapy: Used for ALL standard combination chemotherapies: Systemic depletion of circulating L-asnUsing E.Coli L-asparaginase II enzyme that hydrolysis of L-asn
Long-term regulation of HMG CoA reductase: Inhibition of gene expression by cholesterol
Cholesterol binds to a protein that holds SREBP (sterol regulatory element binding protein) in the ER membrane In the absence of cholesterol, the proteins separate and SREBP is cleaved by proteases A soluble fragment of SREBP diffuses to the nucleus and activates transcription
HMG CoA reductase regulation
Cholesterol or its derivatives inhibit synthesis and stimulate proteolysis of the enzyme. It is *activated* when *dephosphorylated* It is *deactivated* when *phosphorylated*
Which bonds are more fuild: cis or trans
Cis because of the kink in their structure, they can't stack as well as trans (which stack similarly to saturated double bonds)
Vitamin B12 Structure
Cobalamin
hydrocarbons
Compounds composed of only carbon and hydrogen
Ctr1
Copper uptake transporter
Cystinuria
Defects in amino acid transporters SLC7A9 and SLC3A1 This disease is is characterized by the absence of transporter for dibasic amino acids cystine, lysine, arginine, and ornithine in both the small intestine and the kidney. As a result, none of these amino acids are absorbed by the intestine or reabsorbed by the kdiney, producing stones.
Long term regulation of HMG CoA reductase: proteolysis
Degradation of HMG-CoA Reductase is stimulated by cholesterol, by oxidized derivatives of cholesterol, by mevalonate, and by farnesol (dephosphorylated farnesyl pyrophosphate). HMG-CoA Reductase includes a transmembrane sterol-sensing domain that has a role in activating degradation of the enzyme via the proteasome
True or False: Steroids decrease COX-1 activity
False They have no effect on COX-1 they only effect COX-2
Degradation of amino acids
Degradation of amino acids converts the carbon skeletonsto TCA cycle intermediates or precursors to be metabolized to CO2, H2O, or for use in gluconeogenesis Amino acids are glucogenic, ketogenic or both. Glucogenic amino acids-carbon skeletons are broken down to pyruvate, a-ketoglutarate, succinyl-CoA, fumarate, or oxaloacetate (glucose precursors). Ketogenic amino acids, are broken down to acetyl-CoA or acetoacetate and therefore can be converted to fatty acids or ketone bodies.
Tetrahydrofolate pool
Degradation of the amino acids glycine, serine, histidine and tryptophan provides C1 units to tetrahydrofolate. Serine and glycine are more abundant than the two others and therefore are the main sources.
Arachidonic acid synthesis
Derived from Linolenic Acid First a double bond is introduced at position 6 (from carboxy end). Then the chain is elongated by 2 carbons, followed by second desaturation at position 5.
Sites of Action of Leukotriene-Modifying Drugs
Drugs like Singulair act as antagonists to the receptor that binds leukotrienes
Emphysema and alpha 1 antitrypsin
Elastase, a secretory product from neutrophil, is usually inhibited by α1-antitrypsin. Genetic disorder with a deficiency of α1-antitrypsin leads to excessive elastase activity in lung that causes tissue damage and emphysema. Smoking can cause oxidative inactivation of a1antitrypsin (the oxidation of methionine to sulfoxide). The oxidized a1antitrypsin has low affinity to elastase. The result is tissue damage and emphysema in heavy smokers.
What can be a problem in the urea cycle?
Failure of urea cycle leads to the accumulation of carbamoyl phosphate and increases pyrimidine synthesis in cytosol resulting in a buildup of Orotate in blood and in urine. Failure of CPSI leads to low carbamoyl phosphate in cell and may lower Orotate level.
True or False: Excess amino acids cannot be stored as amino acids, but can be excreted in urine.
False They have to be degraded into metabolites to do either of those processes
Which heme related enzymes are inhibited by lead?
Ferrhocheletase ALA dehydratase
Folate and pregnancy
Folate deficiency is uncommon in Western diet. Overcooked food could destroy folate. Folate is needed for the fetus to maintain normal growth and development. Pregnant mother should supplement folate intake daily. Folate deficiency has been implicated to "Neural Tube Defects" - Spina bifida (meningocoel, myelomeningeocoel). The defects commonly arise in the first weeks of pregnancy before a woman may realize she is pregnant. Folate fortification should start early when a woman is planning to have a baby. Folate supplementation has been estimated to reduce more than 50% of the neural tube defects in newborns.
Effect of G6P DH on xenobiotic metabolism
G-6-P dehydrogenase deficiency or inactivation leads to hemolytic anemia caused by oxidative cell damage. G6P DH has low thermal stability (can be inactivated by fever)
γ-Glutamyl transpeptidase
GGT is present in the cell membranes of many tissues, including the kidneys, bile duct, pancreas, gallbladder, spleen, heart, brain, and seminal vesicles. It is involved in the transfer of amino acids across the cellular membrane and leukotriene metabolism. It is also involved in glutathione metabolism by transferring the glutamyl moiety to a variety of acceptor molecules including water, certain L-amino acids, and peptides, leaving the cysteine product to preserve intracellular homeostasis of oxidative stress. This general reaction is: (5-L-glutamyl)-peptide + an amino acid ⇋ peptide + 5-L-glutamyl amino acid
GHRH vs GHRIH
GHRH = growth hormone releasing hormone GHRIH = growth hormone release-inhibiting hormone (somatostatin)
Incretins
GIP and GLP-1 (Glucagon Like Peptide) Incretins are compounds which stimulate insulin release. The incretins are produced from pro-glucagon
What causes bile salts to form?
Gallstones are formed due to cholesterol precipitation in the absence of sufficient bile salts
Glutathione Synthesis
Glutathione is a tripeptide formed with *glutamate, cysteine and glycine*. The peptide bond form on glutamate is on the γ-carboxyl group and not on the α-carboxyl. Small intestine is the major site for synthesis of glutathione. Glutathione serves as a sulfhydryl buffer and antioxidants. Reduced glutathione (GSH) is 500-fold higher than oxidized GSSG inside the cell. Glutathione is a cofactor of *glutathione peroxidase, a selenium enzyme* Glutathione can be used as a high capacity transport system of amino acids.
Pathways to making phospholipids from phosphatidic acid
Glycerol 3-phosphate reacts with fatty acyl CoA to for phosphatidic acid. 2 different mechanisms are then used to add a head group to the molecule (eg. choline, serine, etc) 1. phosphatidic acid is cleaved by a phosphatase to form DAG. DAG then reacts with an activated head group. In the synthesis of phosphatidylcholine, the head group choline is activated by combining with CTP to form CDP-choline. Phosphocholine is then transferred to carbon 3 of DAG, and CMP is released, Phosphatidylethanolamine is produced by a similar reaction involving CDP-ethanolamine 2. phosphatidic acid reacts with CTP to form CDP-diacylglycerol. This compound can react with phosphatidyglycerol (which itself is formed from the condensation of CDP-diacylglycerol and and glycerol 3-phosphate) to produce cardiolipin or with inositol to produce phosphatidylinositol
HMG CoA reductase
HMG CoA reductase is the rate-limiting enzyme in cholesterol biosynthesis. It is the target of the most popular cholesterol lowering drugs (HMG CoA reductase inhibitors or Statins) It is *activated* when *dephosphorylated* It is *deactivated* when *phosphorylated*
Heme
Heme consists of: - One ferrous ion (Fe2+) in the center - Protoporphyrin IX (a tetrapyrrole ring)Heme is the prosthetic group of: Hemoglobin, myoglobin, cytochromes, catalase, tryptophan pyrrolase The role of heme is dictated by the enviroment created by the three dimensional structure of protein
Heme synthesis
Heme synthesis occurs partly in the mitochondria and partly in the cytoplasm. The process begins in the mitochondria because one of the precursors is found only there. Since this reaction is regulated in part by the concentration of heme, the final step (which produces the heme) is also mitochondrial. Many of the intermediate steps are cytoplasmic. Notice in the diagram of the pathway that there is a branch with no apparent useful endproduct
Hemoglobin M disease
Hemoglobin can't bind Fe2+
Circadian Rhythm of BP
Highest in the morning
Folate methyl trap
Homocysteine is the ONLY ACCEPTOR of one-carbon units at the methyl state of oxidation (N5 -methyl tetrahydrofolate). The reaction is catalyzed by the enzyme methionine synthase and requires vitamin B12. In a B12 deficit tetrahydrofolate becomes "trapped" (the folate methyl trap theory) as N5-methyl tetrahydrofolate, because homocysteine cannot accept the the methyl group, and the enzyme that formed N5-methyl tetrahydrofolate from N5, N10-methylene tetrahydrofolate (i.e., N5, N10-methylene tetrahydrofolate reductase) is not reversible N5, N5 -methyl tetrahydrofolate cannot be re-oxidized back to N10-methylene tetrahydrofolate)
GLP-1 receptor agonists
Hypothesis: Factors that increase levels or half-lives might increase insulin secretion from pancreas agonists of the GLP-1 receptor This class of drugs is used for the treatment of type 2 diabetes. One of their advantages over older insulin secretagogues, such as sulfonylureas or meglitinides, is that they have a lower risk of causing hypoglycemia eg. exentatide
IGF vs Insulin
IGF, which is structurally similar to proinsulin, acts by binding to receptors (receptor tyrosine kinase). However, it's affinity to insulin receptor is 100 times less than that of Insulin and it's levels are controlled by six types of binding proteins (IGFBPs). Therefore, IGF has less effect on reducing Glucose levels despite acting as insulin (a weak Insulin like action) than GH which causes increase in Glucose by various mechanisms (Gluconeogenesis, Decreased Glucose uptake aka Insulin resistance). It appears that GH (directly & Indirectly) makes sure that AAs are exclusively used for Protein synthesis by maintaining (high) glucose levels and FFAs (Lipolysis) to be used for energy production.
IGF-1
IGF-1 is produced primarily by the liver as an endocrine hormone as well as in target tissues in a paracrine/autocrine fashion. Production is stimulated by growth hormone (GH) and can be retarded by undernutrition, growth hormone insensitivity, lack of growth hormone receptors, or failures of the downstream signaling pathway. IGF-1 is a primary mediator of the effects of growth hormone (GH). Growth hormone is made in the anterior pituitary gland, is released into the blood stream, and then stimulates the liver to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body, especially skeletal muscle, cartilage, bone, liver, kidney, nerves, skin, hematopoietic cell, and lungs. In addition to the insulin-like effects, IGF-1 can also regulate cell growth and development, especially in nerve cells, as well as cellular DNA synthesis
Tetrahydrofolate trap
In B12 deficiency ,the THF pools are converted to N5-methyl THF and accumulated This is considered as the "Methyl Trap" for FH4 The reaction that converts methylene THF to methyl-THF is irreversible.
mTOR and cancer
In normal cells, mTOR activity is controlled by positive and negative upstream regulators. Positive regulators include growth factors and their receptors, such as insulin-like growth factor-1 (IGF-1) and its cognate receptor IFGR-1, members of the human epidermal growth factor receptor (HER) family and associated ligands, and vascular endothelial growth factor receptors (VEGFRs) and their ligands, which transmit signals to mTOR through the PI3K-Akt. Negative regulators of mTOR activity include phosphatase and tensin homolog (PTEN) that inhibits signaling through the PI3K-Akt pathway, and tuberous sclerosis complex (TSC) 1 (hamartin) and TSC2 (tuberin). Phosphorylation of TSC2 by Akt releases its inhibitory effect on mTOR and up-regulates mTOR activity. Another negative regulator, LKB1, is in an energy-sensing pathway upstream of TSC
Genetically determined causes of pancreatic insufficiency
In the normal pancreas, trypsin resulting from autoactivation of trypsinogen within the pancreatic parenchyma is inhibited by SPINK1 and in the second line by mesotrypsin or trypsin. This defencemechanism prevents the pancreas from activation of the pancreatic enzyme cascade and autodigestion. Condition in inherited pancreatitis: Mutations in CFTRmay disturb this delicate balance by intrapancreaticacidification or by a defective apical trafficking of zymogen granules and thus facilitate the intrapancreatic activation of digestive enzymes. Mutations in SPINK1 lead to an imbalance of proteases and their inhibitors within the pancreatic parenchyma resulting in an inappropriate conversion of pancreatic zymogens to active enzymes with autodigestion and inflammation.
How do cancer cells replenish intermediates?
Increase in glucose and glutamine uptake
Pancreatic lipase/colipase deficiency
Increased TG into colon can lead to diarrhea and steatorrhea
Xenicol, Alli, Alli
Inhibit the action of pancreatic lipase
Hepicidin regulation of iron
Iron deficiency decreases hepcidin expression and increases ferroportin. This increases iron absorption intestine and excretion from macrophage. As a result, more iron is available for making iron containing proteins Iron overload causes high expression of hepcidin which binds and inactivates ferroportin. Less iron is absorbed fromintestine and excreted from macrophage.
Detoxification of acetaminophen
It already has an OH group so you can go directly to phase 2 through glucuronidation or sulfation If you have CYP2E1, a phase 1 reaction can occur to yield NAPQ1 (N-acetyl-P benzoquinoimine)
Ornithine
L-Ornithine is one of the products of the action of the enzyme arginase on L-arginine, creating urea. Therefore, ornithine is a central part of the urea cycle, which allows for the disposal of excess nitrogen. Ornithine is not an amino acid coded for by DNA, that is, not proteinogenic. However, in mammalian non-hepatic tissues, the main use of the urea cycle is in arginine biosynthesis, so, as an intermediate in metabolic processes, ornithine is quite important.
LKB1
LKB1 is a primary upstream kinase of adenosine monophosphate-activated protein kinase (AMPK), a necessary element in cell metabolism that is required for maintaining energy homeostasis. It is now clear that LKB1 exerts its growth suppressing effects by activating a group of ~14 other kinases, comprising AMPK and AMPK-related kinases. Activation of AMPK by LKB1 suppresses growth and proliferation when energy and nutrient levels are scarce. Activation of AMPK-related kinases by LKB1 plays vital roles maintaining cell polarity thereby inhibiting inappropriate expansion of tumour cells
Linoleic acid
Linoleic (ω6) 18:2(Δ9,12)(n-6) Linoleic acid is an essential fatty acid and precursor to Arachidonic acid Arachidonic acid is the precursor of prostaglandins
Where is pyruvate DH located and what does it do?
Located in the mitochondria and converts pyruvate to acetyl CoA
Removal of aa's from serum
Low protein diets Blood transfusion and hemodialysis. Detoxification with reactions of *benzoate* and *phenylbutyrate* (bind amino acids)
Maple Syrup Disease
Maple syrup urine disease is caused by a genetic defect in branched-chain ketoacid dehydrogenase. The lack of metabolic processing of valine, leucine and isoleucine leads to the unusual accumulation of their corresponding α-keto acids.These ketoacids give the urine the characteristic odor for which the disease is named. Treatment includes dietary restriction of these amino acids. In acute case, patient is given a blood transfusion. If the enzymatic defect is related to low affinity to the cofactors TPP, therapeutic doses of thiamine can be given. Untreated infants do not survive long after birth.
Lorcaserin (Belviq)
Mechanism of Action: Serotonin 2C (5-HT2C) agonist: these receptors are located mainly in the brain and thought to increase satiety and pleasure from food. Vs 2B (5-HT2B) agonist which cause valvulopathy in Phen-Fen patients • Pros: appetite suppression/satiety, effect on mood, well tolerated • Cons: single action of weight loss-not able to overcome internal regulatory mechanisms that increase hunger and decrease metabolism over time to account for weight loss. • Contraindications: pregnancy. Precautions: SSRI use (serotonin syndrome), valvular hear disease, memory/mental changes, depression, low glucose, low heart rate, decrease blood cell count-RBC and WBC, nursing, priaprism, increased prolactin•Side effects: dizziness, nausea, fatigue • When to consider:patient who had positive response to Meridia (sirbutramine), "mind hunger"-always thinking about food
ceruloplasmin
Metalloenzyme of copper that converts ferrous to ferric
THF metabolism and chemotherapy
Methotrexate is a structural analogue of tetrahydrofolate. Tetrahydrofolate is the enzyme cofactor for the "Dihydrofolate Reductase", which is important in the biosynthesis of purines and pyrimidines. Methotrexate binds a thousand-fold better than tetrahydrofolate to the enzyme and blocks nucleotide base synthesis, which in turn, inhibits cell growth. This class of drug is referred to anti-metabolite drugs. It slows down cell proliferation.
Porphyria Cutanae Tarda
Most common porphyria Classified as such when Uroporphyrinogendecarboxylase activity <20% Hepatic disorder, autosomal dominant Inherited or obtained through Hepatitis C, drugs, alcohol, poisons Patients are photosensitive (cutaneous photosensitivity)• Accumulation of porphyrinogens results in their conversion to porphyrins by light • Porphyrins react with molecular oxygen to form oxygen radicals • Oxygen radicals can cause severe damage to the skin Treatment: Chloroquine or hydroxychloroquine can move excess porphyrins from the liver and promote excretion.
SPINK1
Mutations in this gene lead to an imbalance of proteases and their inhibitors within the pancreatic parenchyma resulting in an inappropriate conversion of pancreatic zymogens to active enzymes with autodigestion and inflammation.
Which one is toxic: NH4 or NH3?
NH4 It must be converted to UREA and secreted
Nitric oxide
Nitric oxide (NO) is a short-lived signal transduction molecule. NO binds and activates guanylate cyclase through a heme group. Activation of guanylate cyclase increases cyclic GMP level. Nitric oxide is an important biomolecule involved in vasodilation and neural transmission
NBS for metabolic disorders
PKU = phenylketonuriaIncrease in phenylalanine MSUD = Maple syrup urine diseaseIncrease in Ile Homocystinuria = Increase in methionine Acute neonatal citrullinemia = Accumulation of citruline
Xenical/Alli
Pancreatic Lipase inhibitor When patients eat fat, they get immediate diarrhea
Triglycerol hydrolysis
Pancreatic lipase acts preferentially on the 1- and 3-positions of TG It is activated by a co-lipase which relieves inhibition by bile salts. The enzyme acts at the interface of water and oil
VLDL Assembly
Part of the lipid is added while the protein (apo B-100) is being synthesized on the ribozyme. This step requires MTP. The partially lipidatedparticle then fuses with protein-free lipid particle which is formed in smooth ER, to form mature VLDL. If sufficient TG is not available, the apo B-100 is degraded
Complications of Cystic Fibrosis that lead to impairment of digestion, absorption and nutrition (pancreatic insufficiency)
Patients with cystic fibrosis (CF), have a genetic defect in the function of the chloride channels. CF is characterized not only by lung congestion and infection but also by malabsorption of nutrients by the pancreas. Inspissation and precipitation of pancreatic secretions leads to obstruction of pancreatic secretory ducts. The ducts normally carry pancreatic enzymes into the lumen of the small intestines. In CF patients, the pancreatic enzymes are unable to enter the intestinal lumen to digest dietary proteins.
reductase kinase
Phosphorylation of HMG CoA reductase is catalyzed by this enzyme, whose activity is also regulated by phosphorylation.
Porphyrins
Porphyrins are tetrapyrroles They consist of four weakly aromatic pyrrole rings joined by methene bridges. Porphyrins are cyclic compounds that bind metal ions (usually Fe2+ or Fe3+) Different porphyrins vary in the nature of side chains that are attached to each of the 4 pyrrole rings.
PET Scan
Positron Emission Tomography Metabolic changes at the cellular level *Tracer*: Injection of small amounts of a radiotracer (short lived) On a biologically active molecule Imaging of energy released by the tracer *Imaging*: PET-CT (computed tomography) scanner 3D image constructed by computer *Cancer*: most common tracer: glucose analog Based on high glucose intake by cancer cells
ezetimibe
Prevents cholesterol reabsorption --> lower LDL
Oxidation of LDL
Primary catalyst for starting the arteriosclerosis formation They get picked up by acetyl LDLR's
essential amino acids
Private Tim Hall Has A Video Meeting PVT TIM HALL *P*he *V*al *T*hr *T*rp *I*le *M*et *H*is (conditional) a *L*eu *L*ys Has A Video Meeting(lucogenic) These are glucogenic ones His Arg Val Met. Leu and lys are pure ketogenic. And the rest is both keto and glucogenic.
Uroporphyrinogen I synthase and uroporphyrinogen III cosynthase
Production of uroporphyrin III requires two enzymes. The substrates are four molecules of porphobilinogen. *The first reaction* is catalyzed by uroporphyrinogen I synthase. - The porphobilinogen molecules lose their amino groups. - A linear tetrapyrrole with alternating acetic acid and propionic acid groups is produced. This linear molecule cyclizes slowly (nonenzymatically) to yield uroporphyrinogen I. Without the second reaction (below), the heme synthesis pathway would end with porphyrinogens of the I series, which have no known function. *The second reaction* is catalyzed by uroporphyrinogen III cosynthase. This enzyme rapidly converts the alternating linear tetrapyrrole to the cyclic uroporphyrinogen III (pronounce), which has the substituents of its IV ring reversed: AP AP AP PA. This is the physiologically useful product.
Protoporphyrinogen IX oxidase
Protoporphyrinogen IX oxidase converts the methylene bridges between the pyrrole rings to methenyl bridges. Resonance of double bonds around the entire great ring, with its resulting stabilization, is now possible
microcytic anemia
RBC become small and pale Deficiency in iron, copper and peroxidine
regulation of step 1 of heme synthesis
Regulation occurs through control of gene transcription. Heme functions as a feedback inhibitor, repressing transcription of the ALA Synthase gene in most cells. When heme (end product) is produced in excessive amounts, heme is converted to hemin. Hemin decreases action of ALA synthase in liver. (end product inhibition). The reverse occurs when heme biosynthesis is reduced. Drugs as grisofulvin (antifungal), hydantoin & phenobarbital (anticonvulsant) increase ALA synthase activity: as these drugs are metabolized by cytochrome p450 in liver resulting in more consumption of heme (component of cytochrome). Accordingly, heme concentration is reduced resulting in stimulation of action of ALA synthase.
Hyperammonemia
Results in excess NH4+ which depletes a-ketoglutarate leading to inhibition of the TCA cycl
________________ is regenerated through methionine synthesis from homocysteine catalyzed by methionine synthase using N5 methyl THF and methylcobalamin B12 as cofactor
S-adenosylmethionine
Methionine is linked to adenosine to form ____________________
S-adenosylmethionine (SAM)
What is the universal methyl group donor?
SAM
S-adenosylmethionine
SAM can be converted to homocysteine for cysteine synthesis made from ATP and methionine. Used as a donor for methyl. Only one methyl on the molecule
SCAP
SREBP cleavage-activating protein SCAP has a transmembrane sterol-sensing domain homologous to that of HMG-CoA Reductase. When bound to a sterol, the sterol-sensing domain of SCAP binds the ER membrane protein Insig. Association with Insig causes the SREBP-SCAP precursor complex to be retained within the ER. When sterol levels are low, SCAP and Insig do not interact. This allows the SCAP-SREBP precursor complex to translocate from the ER to the golgi apparatus.
Iron Responsive Element (IRE)
Same as aconitase a short conserved stem-loop which is bound by iron response proteins (IRPs, also named IRE-BP or IRBP). The IRE is found in UTRs (untranslated regions) of various mRNAs whose products are involved in iron metabolism. For example, the mRNA of ferritin (an iron storage protein) contains one IRE in its 5' UTR. When iron concentration is low, IRPs bind the IRE in the ferritin mRNA and cause reduced translation rates. In contrast, binding to multiple IREs in the 3' UTR of the transferrin receptor (involved in iron acquisition) leads to increased mRNA stability.
Acetyl LDLR/Scavenger receptors
Scavenger receptors are a group of receptors that recognize modified low-density lipoprotein (LDL) by oxidation or acetylation. This naming is based on a function of cleaning (scavenging): Scavenger receptors widely recognize and take up macromolecules that have a negative charge, like modified LDL.
Reactions of fatty acyl synthase
Sequential addition of 2 carbon units to acetyl CoA (as malonyl CoA). After 7 cycles, the 16 carbon FA (palmitate) is released from the enzyme. The methyl group of the first acetyl CoA becomes the methyl group of the palmitate
What are the 3 series of Eiconasoids?
Series 1: Derived from 20:3 fatty acid *Series 2: Derived from 20:4 fatty acid (arachidonic)* Series 3: Derived from 20:5 fatty acid Each number stands for how many double bonds are located outside of the ring structure
Cysteine is derived from...
Serine and homocysteine The sulfur atom is from homocysteine and the carbon backbone is from serine.
Eiconasoids
Signaling molecules derived from 20-carbon fatty acids (eicosa= 20) Produced in most cells Very short half life (seconds to minutes) Potent mediators of inflammatory response Blame them for pain, swelling, fever, allergic reactions
mTOR pathway
Starvation (high AMP/low ATP) → Activation of TSC1/TSC2 → Inactivation of mTOR kinase by Rheb → less mTOR → *AUTOPHAGY* Growth Factors → Inactivation of TSC1/TSC2 → Activation of mTOR kinase by Rheb → more mTOR → *No AUTOPHAGY*
Gaucher's Disease
Symptoms: Liver and spleen enlargement, erosion of long bones and pelvis, mental retardation in infantile form only Principal storage substance: Glucocerebroside Enzyme Deficiency: Glucocerebrosidase
Niemann-Pick disease
Symptoms: Liver and spleen enlargement, mental retardation Principal storage substance: Sphingomyelin Enzyme Deficiency: Sphingomyelinase
Tay-Sach's Disease
Symptoms: Mental retardation, blindness, cherry red spot on macula, death 2-3 y.o. Principal storage substance: Ganglioside Gm2 Enzyme Deficiency: β-Hexosaminidase A
Fabry's disease
Symptoms: Skin rash, kidney failure, pain in lower extremities Principal storage substance: Ceramide trihexoside Enzyme Deficiency: α-Galactosidase A
Tetrahydrofolate
Tetrahydrofolate (FH4) is formed from reduction of folate by *dihydrofolate reductase* using *NADPH* as cofactor. The one-carbon units for carbon transfer reaction are attached at *N5-N10* position
Step 2 of Heme synthesis
The ALA dehydratase reaction occurs in the cytoplasm; the product is porphobilinogen The substrates are two molecules of *ALA*. The reaction is a condensation to form *porphobilinogen*, the *first pyrrole* Two molecules of water are released. The asymmetry of the reaction relative to the two molecules of substrate results in the pyrrole ring having two different substituent groups: acetic acid propionic acid.
7-α-hydroxylase
The enzyme for the rate limiting step of bile salt production converts cholesterol to 7-α-hydroxy cholesterol
Heme Degradation
The first reaction is cleavage of the heme ring by a microsomal heme oxygenase - the product is biliveridin In the second reaction biliverdin reductase reduces the central methene bridge of biliverdin, producing bilirubin. - Conversion of biliverdin to bilirubin requires NADPH as a reducing agent
Thyroid Hormone synthesis
The first step in the synthesis of thyroid hormones is the organification of iodine. Iodide is taken up, converted to iodine, and then condensed onto tyrosine residues which reside along the polypeptide backbone of a protein molecule called thyroglobulin. This reaction results in either a mono-iodinated tyrosine (MIT) or di-iodinated tyrosine (DIT) being incorporated into thyroglobulin. This newly formed iodothyroglobulin forms one of the most important constituents of the colloid material, present in the follicle of the thyroid unit. The other synthetic reaction, that is closely linked to organification, is a coupling reaction, where iodotyrosine molecules are coupled together. If two di-iodotyrosine molecules couple together, the result is the formation of thyroxin (T4). If a di-iodotyrosine and a mono-iodotyrosine are coupled together, the result is the formation of tri-iodothyronine (T3). From the perspective of the formation of thyroid hormone, the major coupling reaction is the di-iodotyrosine coupling to produce T4. Although T3 is more biologically active than T4, the major production of T3 actually occurs outside of the thyroid gland. The majority of T3 is produced by peripheral conversion from T4 in a deiodination reaction involving a specific enzyme which removes one iodine from the outer ring of T4. The T3 and T4 released from the thyroid by proteolysis reach the bloodstream where they are bound to thyroid hormone binding proteins. The major thyroid hormone binding protein is thyroxin binding globulin (TBG) which accounts for about 75% of the bound hormone.
Pepsinogen
The inactive form of pepsin that is first secreted by specialized (chief) cells located in gastric pits of the stomach.
Coproporphyrinogen III oxidase
The mitochondrial enzyme, coproporphyrinogen III oxidase, catalyzes the next reaction. The substrate is coproporphyrinogen III. The reaction is conversion of the propionic acid groups of 2 of the 4 rings to vinyl groups. We now have the final substituent pattern of MV MV MP PM (note that "Petrarchan" pattern of the last four substituent groups). The product is protoporphyrinogen IX
Alkaptonuria
The physical symptoms from baby with alkptonuria is black decoloration of urine collected in diaper.Alkaptonuria is a *autosomal recessive* inherited disorder, that is caused by the defects in the enzyme *homogentisic acid oxidase*. This enzyme breaks down a toxic tyrosine byproduct, homogentisic acid (also called alkapton). Build-up of homogentisic acid is harmful to the bones and cartilages. Homogentisic acids slowly and progressively get deposited in bones and cartilage where it turns into a pigmented polymeric materials. This deposit with yellow or ochre-colored pigment is called Ochronosis. In adult, the most obvious sign is a thickening and blue-black discoloration of the ear cartilage. When this pigmented materials are excreted in urine and impart the black color. Alkaponuria is a life-long disease with no cure for the condition. Treatment includes ?*restriction of phenylalanine and tyrosine* in diet to slow down the progress of the disease. Vitamin C also seems to slow down the formation of the polymeric deposits.
enterohepatic circulation
The process of bile reabsorbed from the sm intestine and returned to the liver by the portal vein and reused
carbamoyl
The univalent carboacyl group formed by loss of -OH from the carboxy group of carbamic acid
What is the commonality among lipids?
Their solubility in organic solvents
Fibroblast Growth Factor 23
There is a hormone called _______________ which lowers calcium by inhibiting vit d production which lowers ability of absorbing Ca & Phosphate in the Gut.
Thiopurine chemotherapy in acute lymphoblastic leukemia
Thiopurine is a chemo-therapeutic agent for treatment of leukemia. Thiopurine- S-methyltransferase (TPMT) is a polymorphic enzyme that catalyzes the S-methylation of thiopurine, which is the inactivation pathway in hematopoietic tissues. For the genetic polymorphism, patients who inherit two nonfunctional TMPT alleles will develop dose-limiting hematopoietic toxicity. They tolerate 5 -10% standard dosage. Heterozygous patients are treated with a modest dosage. Concurrent thiopurine therapy and cranial irradiation for ALL patients with TPMT-deficiency (homo- and heretozygous) have higher frequency of developing malignant brain tumor at a later age
α-linolenic acid
This fatty acid has 18:3(9, 12, 15); a ω-3 fatty acid; *essential FA*
Ornithine transcarbomylase
Transfers the carbomoyl group of carbomyl phosphate to ornithineto make citrulline Reaction occurs in mitochondrion Ornithine produced in the cytosol enters via a specific transport system Citrulline is exported from the mitochondria.
ABCG5/G8
Transports cholesterol out of the cell *Transports more plant sterol than cholesterol* β-sitosterolemia is a disorder involving this transporter
How do you think episodes of acute neurological symptoms would be treated?
Treatment is by injection of hemin (a form of heme).Why would this work? The heme, in addition to supplying needs, would repress transcription of the gene for ALA Synthase, rate-limiting for the pathway and the source of excess ALA
True or False: All tissues can synthesize cholesterol, but only liver can degrade it. Therefore it is necessary for the excess cholesterol from peripheral tissues to be transported to liver for disposal.
True
True or False: FGF-23 inhibites 1-α-Hydroxylase
True Therefore there is no active Vitamin D
True or False: All CytP450 enzymes require NADPH
True This is why Glucose-6-Phosphate DH is so important It is the initial enzyme of the pentose phosphate shunt and produces NADPH
True or False: Animals cannot introduce double bonds between the 9th and 18th carbon of de novo FA's. Only plants can.
True this is why there are essential FA's. Essential FA's = Linoleic acid (ω6) 18:2 (Δ9,12)(n-6) Arachidonate (ω6) 20:4 (Δ5,8,11,14) (n-6) Linolenic acid (ω3) 18:3 (Δ9,12,15) (n-3)
Phenylalanine is converted to...
Tyrosine *Phenylalanine hydroxylase* converts phenylalanine to tyrosine. The reaction requires biopterin as a cofactor, which is similar to folic acid but is not a vitamin. It is synthesized from GTP. Phenylalanine cannot be synthesized from tyrosine. The reaction is not reversible i.e. phenylalanine is an essential amino acid.
Calorigenic effect of T3
T3 increases heat production by increasing fuel oxidation which itself generates heat T3 increases release of norepinepherine(sympathetic neurones), which *increases cell permeability to Na* (skeletal muscle), Na,K-ATPase stimulated, ATP consumed, thus more ATP generated by fuel oxidation. Longer term increases in Na,K-ATPase expression and other enzymes.
UDP-glucuronic acid
UDP-glucuronic acid is the glucouronyl donor in phase 2 xenobiotic metabolism
Where is the Urea Cycle?
Urea cycle operatesonly in liver to removeammonia in the formof urea
Uroporphyrinogen decarboxylase
Uroporphyrinogen decarboxylase decarboxylates the acetyl side chains, converting them to methyl groups
Glutamine
What AA is the major carrier of nitrogen byproducts from most tissues in the body? brings ammonia from the brain and skeletal muscle to the kidney
Autocrine
What Cell Signaling Mechanism is being used when a single cell in a mixed population secretes ligands that bind only to its own receptor?
Paracrine
What Cell Signaling Mechanism is being used when a single cell in a mixed population secretes ligands that bind only to other phenotypically different cells?
hepcidin
What hormone from the liver blocks the release of iron from intracellular stores to help maintain iron homeostasis and protect against invasion by pathogenic bacteria?
Phosphatidic acid
What is formed when one alcohol group of glycerol is esterified by a phosphoric acid rather than by a carboxylic acid?
fluorodeoxyglucose
What radioactive substance is used most commonly in positron emission tomography? gets phosphorylated by hexokinase and trapped in the cell
Role of Glutamate in Urea cycle
When acidosis occurs the body will divert more glutamine from the liver to the kidney. This allows for the conservation of bicarbonate ion since the incorporation of ammonia into urea requires bicarbonate (see below). When glutamine enters the kidney, glutaminase releases one mole of ammonia generating glutamate and then glutamate dehydrogenase releases another mole of ammonia generating 2-oxoglutarate (α-ketoglutarate). The ammonia will ionizes to ammonium ion (NH4+) which is excreted. The net effect is a reduction in the concentration of hydrogen ion, [H+], and thus an increase in the pH
When does citrate translocation take place?
When there is a lot of ATP This makes sense because Citrate is translocated when FA synthesis (energy storage) occurs
Chymotrypsinogen
When this proenzyme comes in contact with trypsin in the small intestine, it is converted into active chymotrypsin
5-Lipoxygenase
Which enzyme converts Arachidonic acid in to leukotriene A4
Why is low does aspirin good for you?
While low does aspirin irreversibly inhibits COX in both platelets and endothelial cells (EC), the anucleated platelets cannot recover from the inhibition, while EC can synthesize new enzyme and therefore produce PGI2
ATP7B
Wilson disease protein (WND), also known as ATP7B protein, is a copper-transporting P-type ATPase which is encoded by the ATP7B gene. ATP7B protein locates in trans-Golgi network of liver and brain, balances the copper level in the body by excrete excess copper into bile and plasma. It is in here that copper binds with ceruloplasmin
Menke's disease
X-linked recessive CT disease by impaired Copper absorption and transport due to defective ATP7A protein leading to decreased lysyl oxidase activity, what is the disorder?
If you don't have MTP, what is the effect?
You can't make chylomicrons
respiratory distress syndrome
a condition that is related to a deficiency in the synthesis of a substance known as lung surfactant. The major constituents of surfactant are *dipalmitoylphosphatidylcholine*, *phosphatidylglycerol*, apoproteins, and cholesterol
Wilson's Disease
a movement disorder caused by an autosomal recessive disorder in the metabolism of copper and defects in Ceruloplasmin mutation in *ATP7B*: an ATP-mediated Hepatocyte Copper transporter Decreased ceruloplasmin because it cannot be secreted without incorporated copper leads to copper mediated hydroxyl free radical tissue damage
γ-Glutamyl Cycle
a proposed pathway for the glutathione-dependent transport of certain amino acids (most notably L-cystine, L-methionine, and L-glutamine) and dipeptides into certain cells; this cycle requires the formation of γ-glutamyl amino acids and γ-glutamyl dipeptides as well as a protein for the translocation of these di- and triisopeptides into the cells.
β-sitosterolemia
a rare autosomal recessively inherited lipid metabolic disorder. It is characterized by hyperabsorption and decreased biliary excretion of dietary sterols leading to hypercholesterolemia, tendon and tuberous xanthomas, premature development of atherosclerosis, and abnormal hematologic and liver function test results.
Ubiquitin
a small protein (76 amino acids) that targets intracellular proteins for degradation by covalently binding to the amino group of lysine residues
Methotrexate
a substrate analogue of tetrahydrofolate and is used as chemotherapeutic agent to treat cancer or auto-immuno diseases.
apoB48
a truncated version of apoB100 (made in liver) It is produced only in the intestines apo B100 is modified at *residue 6666* from CAA to UAA, thereby creating a premature stop codon It does not have the LDL receptor recognition site and thus chylomicrons cannot bind to those receptors mediates chylomicron secretion from enterocyte to lymphatic system
Direct effects of GH
a) Diabetogenic by decreased glucose uptake into cells (it increases glucose levels despite an insulin increase by inducing insulin resistance in peripheral tissues) b) Lipolysis c) Production of IGF from Liver
Serpins
act either as a transition state analogue or a suicide inhibitor for the targeted proteases. In the case of a1antitrypsin and antithrombinIII, the inhibitor is cleaved by the protease but it traps the protease by forming a tight complex without releasing the enzyme.
Amino acids enter enterocyte via __________ that requires energy from Na+gradient
active transport
Ferrocheletase
adds Fe++ to protoporphyrin IX inhibited by *lead*
What is needed for chylomicron hydrolysis
apoCII apoCII and apoE are transferred to chylomicrons by HDL
nitric oxide is synthesized from...
arginine; the reaction is catalyzed by NO synthase
What foods have potassium?
bananas, oranges, refried beans, *potatoes* and chocolate soaking food in water can reduce potassium (dialyzing/leaching the potato)
Why would barbiturates and ethanol exacerbate the symptoms of acute intermittent porphyria
because they use up heme thereby increasing the production of ALA and PBG
Whipple's disease
blocks lymph circulation and can lead to diarrhea and steatorrhea
Monoamine Oxidase Inhibitor
blocks the enzyme that metabolizes serotonin. Increasing availability of these neurotransmitters in the CNS and peripheral autonomic nervous system. Not often used-side effects, lethal in overdose, difficult dosing, tyramine free. `
lysine is the precursor of...
carnitine
Carbonic Anhydrase
catalyzes the rapid interconversion of carbon dioxide and water to bicarbonate and protons (or vice versa), a reversible reaction that occurs relatively slowly in the absence of a catalyst
Acetyl CoA carboxylase
catalyzes the rate-limiting step in fatty acid synthesis coverts acetyl CoA --> malonyl CoA Formation of malonyl CoA from acetyl CoA represents the first committed step in FA synthesis (Requires Biotin) The polymerization (activation) of ACC is *stimulated by citrate* and *inhibited by palmitoyl CoA*, the end product Insulin stimulates ACC by dephosphorylation Glucagon and epinephrine inhibit it by phosphorylation High Insulin/glucagon ratio induces synthesis of new ACC
mTOR
central regulator of cell proliferation, angiogenesis, and cell metabolism
desferioxamine
chelates free iron and is a treatment for iron overdose
xenobiotics
chemical substances that are foreign to the biological system
Hydrolysis of cholesterol esters
cholesterol esters are hydrolyzed my *cholesterol esterase*
UDP glucuronosyltransferase
conjugation of bilirubin catalyzes the transfer of two glucuronic acid groups sequentially to the propionic acid groups of the bilirubin. The major product is bilirubin diglucuronide
Procarboxypeptidase
converted to carboxypeptidase by trypsin
Where does FA synthesis take place?
cytoplasm and mostly in the liver
ALA Synthase deficiency
deficiency my cause Sideroblastic Anemia X-linked responds to pyridoxine treatment
Benecol
drug used to lower cholesterol displaces cholesterol from the micelle so that cholesterol can't be absorbed
lipoprotein lipase
enzyme that breaks down triglycerides into fatty acids and glycerol; attatched to the cell membranes of cells that line the blood vessels
Cytochrome P450
enzymes in Phase I metabolism of xenobiotics and prescription drugs. Cytochrome P450s oxidize drug molecule by introducing oxygen, hydroxyl group which alters the property and solubility of the molecule in blood.
Cox-1
found widely in the body and tends to be expressed constantly as a normal part of the functioning of the body. It is especially common in the digestive tract. Notably, in the stomach it produces prostaglandins that inhibit the secretions of stomach acid. Because inhibition of COX-1 activity in the gut is associated with NSAID-induced ulcerations, pharmaceutical companies have developed drugs targeted exclusively against the inducible COX-2 activity
GIP
gastric inhibitory peptide activated by glucose, fat, amino acid, stimulates insulin release inhibits gastric emptying and acid
Hartnup's disease
gene SLC6A19 a genetic disorder characterized by the inability of intestinal and renal epithelial cells to absorb neutral amino acidsfrom the lumen. The intestinal defect results in mal-absorption of free amino acids from the diet. *The defect does not affect absorption of peptides*. The kidney defect causes excretion of amino acid in urine (hyperaminoaciduria). • Clinical symptoms are similar to those due to deficiency in essential amino acid and nicotinamide, the pellagra-like features. The lack of tryptophan reduces the synthesis of nicotinamide. Symptoms include photosensitive dermatitis, ataxia, neuropsychiatric symptoms
Porphyrias
genetic diseases in which activity of one of the enzymes involved in heme synthesis is decreased (e.g., PBG Synthase, Porphobilinogen Deaminase, etc...) Porphyria means purple color caused by pigment-like porphyrins in urine of patients
Glutamine synthase
glutamate + NH3 --> Glutamine + H20
Adipose tissue lacks ___________. It can make ___________ only from glycolytic pathway. This ensures that the fatty acids are stored only in the fed state
glycerokinase glycerol-3-P
Serine is converted reversibly to ___________
glycine in a reaction that requires pyridoxal phosphate and *tetrahydrofolate*
What do bile salts do?
help emulsify the fats so that the lipolytic enzymes can act more efficiently
glycine is the precursor to...
hemoglobin & creatinine glycine → guanadoacetate → creatine (SAM donates methyl)
Physiological jaundice and Crigler-Najjarsyndrome
hepatic jaundice • Conjugation is impaired. No UGT glucuronosyltransferase • Unconjugated bilirubin is retained by the body. • Kernicterus
Gilbert's disease
hepatic jaundice • may be caused by an inability of the hepatocytes to uptake bilirubin from the blood • As a result, unconjugated bilirubin accumulates.
Phase 1 of xenobiotic metabolism
hydrolysis, oxidation or reduction
glucose alanine cycle
in skeletal muscle glutamate is made and gets converted into alanine via transaminase reaction with pyruvate (important molecule in the transport of amino groups to the liver)
Trypsinogen
inactive form of trypsin secreted by pancreas; activates other enzymes activated by enteropeptidase
cytochrome b5 reductase deficiency
inherited cause of methemoglobinemia treatment: methylene blue or ascorbic acid
methemoglobinemia
intestinal bacteria can reduce nitrates to nitrites: NO3- → NO2- HEMOGLOBIN → METHEMOGLOBIN
creatine clearance
is a measure of kidney function. Normal creatinine is 20-80 mmol/L. High plasma creatinine indicates renal failure
omega (ω) carbon
last carbon on chain, furthest from acid end, start counting from omega end to first double bond
What is an increased excretion of ALA in urine indicative of?
lead poisoning lead binds to the Zn++ binding site located on ALA dehydratase and inhibits the enzyme
NPC1L1 transporter
located on the lumenal membrane and pumps cholesterol into the cell Binds ezetimibe
Statins
lower cholesterol in the blood and reduce its production in the liver by blocking the enzyme that produces it (HMG CoA Reductase)
How do alpha-Ketoglutarate levels change in Hyperammonemia?
lowered
Carnosine
made from histidine and is found in the skeletal muscle, cardiac muscle and brain, kidneys and stomach protects good cells from the bad (free radical damage)
methemoglobin reductase
maintains hemoglobin iron in the 2+ ferrous state It is defficient in infants
transferrin receptor
membrane protein. mediates Transferrin binding and endocytosis/cell-entry
Where is glucose converted to acetyl CoA?
mitochondria thus, there must be a way for acetyl CoA to be transferred to the cytoplasm
What does having a large waist circumference mean for BMI interpretation?
move the patient up 1 BMI class
PCSK9 inhibitors
novel agent -> block PSCK9 which normally degrades LDLR ->> reduce LDL levels by allowing more LDLR to take LDL out of circulation; similar mutations -> low mutations and reduced CAD risk
Step 1 of heme synthesis
occurs in the mitochondria The substrates are: - succinyl CoA (from the tricarboxylic acid cycle) - glycine (from the general amino acid pool) Enzyme: ALA synthase
Proelastase
pancreatic enzyme that is activated by trypsin to make elastase, which is an endopeptidase.
What is tyrosine derived from?
phenylalanine
Hydrolysis of phopholipids
phospholipids are hydrolyzed by phospholipase A2
transferrin
plasma protein that binds and transports *ferric* iron
ferritin
primary iron storage protein; soluble in blood; serum level reflects marrow storage iron
alpha 1 antitrypsin
protease inhibitor belonging to the serpin superfamily it inhibits *trypsin* and *elastase*
ALA Synthase
rate-limiting enzyme of heme synthesis
Cox-2
released mainly by special, inflammatory cells, and its expression is induced by molecules such as various inflammatory paracrines. Glucocorticoids*, which are often used as powerful anti-inflammatory drugs, repress the expression of COX2
Microsomal Triglyceride-transfer protein (MTPs)
required in the formation of chylomicrons The microsomal triglyceride transfer protein helps produce beta-lipoproteins, which are molecules that consist of proteins combined with cholesterol and particular types of fats called phospholipids and triglycerides. These beta-lipoproteins contain the protein apolipoprotein B, which is critical for the creation of molecules called chylomicrons.
Desaturation of FA's
requires molecular oxygen, NAD(P)H, and cytochrome b5 Takes place in ER
SREBP
responsible for cholesterol synthesis; a trascription factor resides in ER membrane until cholesterol starvation; moved by copII coated vesicles to golgi, eventually to nucleus where it initiates the transcription of LDL receptor, HMG CoA Reductase, and HMG CoA Synthase
Tryptophan is the precursor of...
serotonin → melatonin
GLP-1
simultaneously increases insulin release and inhibits glucagon release
Lipoproteins
spherical particles Their external monolayer of a contain free cholesterol, phospholipids, and apoproteins. Cholesterol esters and triacylglycerols are located in the particle core
Secretin
stimulates secretion of bicarbonate (by pancreas), to neutralize the acidity of intestinal contents, so that the pancreatic enzymes can act optimally.
Cholecystokinin
stimulates secretion of bile by gall bladder, and hydrolytic enzymes by pancreas, and inhibits gastric motility.
Phase 2 of xenobiotic metabolism
sulfation, methylation, glucuronidation, Conjugation with glutathione, acetylation
Prostaglandin I2
synthesized by endothelial cells; vasodilator, inhibits platelet aggregation
Thromboxane A2
synthesized by thromboxane synthase, produced vasconstriction, platelet aggregation, and bronchoconstriction
Biosynthesis of Prostaglandins
take arachidonic acid and cyclooxygenase converts it into via synthase into three reactions forming - Prostacyclins, prostaglandins, thromboxanes
Neonatal Jaundice
the breakdown of fetal hemoglobin as it is replaced with adult hemoglobin
Why do patients with renal disease get anemic?
the kidneys produce *erythropoietin* • Uremic toxins inhibit erythropoiesis and reduce life span of RBC • Iron deficiency and inflammation are factors • treat with oral or IV iron and IV or SC erythropoietin
Transamination
the major process for removing nitrogen the process whereby an amino group is combined with a keto acid to form an amino acid?
Endopeptidases are produced by _____________ while exopeptidases are produced by ____________
the pancreas epithelial cells
chylomicron remnant
the remainder of a chylomicron after the triglycerides have been extracted is called this. They are removed and degraded by the liver
1-α-Hydroxylase
the renal enzyme which participates in the conversion of 1,25-hydroxycholecalciferol into 1,25-dihydroxycholecalciferol and 24,25-dihydroxycholecalciferol.
ceramide
the simplest sphingolipid which has a H atom as its head group
Pancreatic Insufficiency
the inability of the pancreas to produce and/or transport enough digestive enzymes to break down food in the intestine and facilitate absorption of nutrients. It typically occurs as a result of progressive pancreatic damage. Discoveries of trypsinogen and trypsin inhibitor mutations in patients with chronic pancreatitis (CP) support the hypothesis that an inappropriate activation of pancreatic zymogens to active enzymes within the pancreatic parenchyma starts the inflammatory process.
Tyrosine is a precursor of...
thyroxine (T3, T4), dopamine, epinephrine, norepinephrine and melanin.
True or False: Glucagon has no effect on skeletal muscle
true there are no glucagon receptors on skeletal muscle
Low pH promotes what 2 cancer hallmarks?
tumor invasion and immune evasion the pH drop is due to anaerobic lactate production
Trypsin inhibitor
used to block accidental activity of trypsin zymogen prevents premature activation of these potentially pancreas-digesting enzymes within the pancreatic ducts.
What is the typical blood cholesterol for a patient heterozygous for Familial Hypercholesterolemia (Type IIa familial dyslipidemia)?
~300 mg/dL
α-Linolenic acid
α-Linolenic (ω3) 18:3 (Δ9,12,15) (n-3)
What substrate does HMG CoA reductase act on? What product does it produce?
β-Hydroxy-β-methyl-glutaryl CoA Mevalonate
Bilirubin
Bilirubin is highly lipid soluble. This property determines its behavior and its further metabolism. Its lipid solubility dictates • that it must be transported in the blood by a carrier; the physiological carrier is serum albumin. • that it is soluble in the lipid bilayers of cell membranes. Bilirubin must be conjugated to a water-soluble substance. This increased its water solubility eases its excretion
Osteromalacia
Nutritional rickets - Vitamin D deficiency - Rickets in children - Osteomalacia in adults Renal rickets (renal osteodystrophy) - Chronic renal failure - Decreased conversion of active form of calcitriol. Hypoparathyroidism - Lack of parathyroid hormone causes hypocalcemia and hyperphosphatemia. - Pseudohypoparathyroidism - Failure of receptor responses due to G-protein asubunit defect.
Phentermine/Topiramate (QSYMIA)
Phentermine: Shorter term appetite suppression and increased satiety (decrease in neuropeptide Y and increase in Leptin). Topiramate: long term appetite suppression, insulin resistance improvement (originally researched as a diabetes medication in the 1980's) • Pros: Dual action on weight control mechanism • Cons: REMS increased risk of orofacial clefts in infants exposed to Qsymia during the first trimester of pregnancy, dosing schedule, SE's. • Contraindications: Glaucoma, CVD/HTN, pregnancy, MAO-I • Side effects: dry mouth, tingling, constipation, memory loss • When to consider: patient with seizures, migraines—topiramate is a better weight alternative
Phenylketonuria (PKU)
is a genetic disorderassociated with the inability to convert phenylalanine to tyrosine by phenylalanine hydroxylase with the accumulation of toxic intermediate (also impairment of cerebral energy metabolism), phenylpyruvate and high concentration of phenylalanine. In infants, this affects brain development and leads to mental retardation. The patient will be supplemented with tyrosine but phenylalanine-restricted diet. After the development of the brain, the normal low protein diet can be used in adult. During pregnancy, affected female individual will resume the phenylalanine-restricted diet to protect the brain development of the fetus
Peritoneal Dialysis
• Uses individuals own peritoneal membranes to filter blood • Infuse 1-3 liters of sterile fluid into the peritoneal cavity via catheter placed in the abdomen • Remove solutes and water primarily by diffusion across a semipermeable membrane • Perform dialysis at home daily
Dialysis
• Movement of solute and water through a semipermeable membrane • Hemodialysis demonstrated for simplicity • Peritoneal dialysis is the other major form
Dubin-Johnson syndrome
• Inability of the hepatocytes to secrete conjugated bilirubin after it has been formed. • Conjugated bilirubin returns to the blood
Multiple Myeloma
• Multiple myeloma is the most common form of symptomatic monoclonal gammopathy. It is characterized by *multiple tumorous masses of neoplastic plasma cells scattered through-out the skeletal system*, which morphologically show up as multifocal destructive bone tumors. • *Patients typically present with back pain, lytic bone lesions, hypercalcemia, renal insufficiency and anemia.* • The bone lesions appear radiographically as punched-out defects in 1-4 cm.This bone lesions progressively destroy the bony cortex, often leading to pathologic fractures
What regulates Carbamoyl Phosphate Synthetase I
• Carbamoyl phosphate synthetase I is allosterically activated by N-acetylglutamate • N-acetylglutamate is synthesized from glutamate and acetyl-CoA by N-acetylglutamate synthase, it is hydrolyzed by a specific hydrolase. • Rate of urea production is dependent on N-acetylglutamate • When aa breakdown rates increase, excess nitrogen must be excreted. This results in increase in Glu through transamination reactions. • Excess Glu causes an increase in N-acetylglutamate which stimulates CPS Icausing increases in urea cycle.
Increase in protein catabolism leads to
• Illnesses/hospitalizations/comorbid conditions • Metabolic acidosis • Catabolic effects of hormones (PTH, cortisol, glucagon) • dysfunction of the growth hormone/insulin growth factor endocrine axis
Reason for lower BUN
• Lower BUN • Decreased protein intake • increased residual renal function • increased treatment efficiency • liver disease
Paget's Disease
• Rapid bone remodeling with over active osteoclastsdissolving bone and replace with vascular fibrous tissue. Serum alkaline phosphatase may be raised. • Major symptom is pain. Skull shows sclerosis and bone expansion. Bone with rapidcalcium isotope uptake shown in isotope bone scan. Affect European countries more. • Other complication may be deafness, nerve compression, tumors and cardiac failure.
Hemodialysis
• AV fistula or graft usually in forearm for arterial and venous access • 4 hour treatment, three times a week • Semipermeable membrane, remove metabolites by diffusion, ultrafiltration and osmosis
NALTREXONE/BUPROPION
• Bupropion -Most widely prescribed antidepressant, also used for smoking cessation • Naltrexone—used in opioid and alcohol addiction • Primary function/ PROS: • Increases activity of POMC cells•NB combinationresults in greater activation of POMC cells, which may translate toweight loss in vivo • Both actions produce synergistic effects that lead to decreased food intake and possibly weight loss • Reduces appetite and increases metabolism •Primary side effects: Nausea, constipation, vomiting, dizziness,and dry mouth •Contraindications: History of: Uncontrolled Hypertension, Heart Disease, Stroke, Seizures, glaucoma, bipolar d/o
Functions of the Kidney
• Excretion of metabolic waste products (urea, creatinine, uric acid) • Elimination and detoxification of drugs and toxins • Maintenance of volume and ionic composition of body fluids • Regulation of systemic blood pressure • Production of erythropoietin • Control of mineral metabolism through endocrine synthesis (1,25-dihydroxycholecalciferol, 24,25-dihydroxycholecalciferol) • Degradation and catabolism of peptide hormones and low-molecular weight proteins • Regulation of metabolic processes such as gluconeogenesis and lipid metabolism
Gigantism vs Acromegaly
• Gigantism, GH in excess before closure of long bone growth centers • Acromegaly, GH chronic excess secretion after closure of the centers
Reasons for higher BUN
• Increased dietary protein • hypercatabolic state • gastrointestinal bleeding (Extensive bleeding into the gastrointestinal (GI) tract will also cause an elevated BUN because digested blood is a source of urea. For example, a hemorrhage of one liter of blood into the GI tract may elevate the BUN up to 40mg/ml) • decreased residual renal function • poor treatment efficiency
Potassium in dialysis patients
• Need adequate renal function to maintain normal levels • High levels can cause cardiac arrest • Other factors affect potassium homeostasis such as medications and diet • Potassium content of food, method of preparation and serving size are all important factors in planning a potassium restricted diet
Protein catabolism
• Nitrogen containing metabolites such as urea, larger peptides and amino acids • Excretion of these compounds is reflected in the BUN or blood urea nitrogen levels • also generates acid (1meq/kg/day) • *urea generation is related to the protein catabolic rate (PCR)* • Protein intake of *1.1 g/kg/day* needed to maintain positive nitrogen balance • Patients who ingest less than *0.8g/kg/day* of protein have a relatively high morbidity and mortality • one way to detect protein malnourished patients is to calculate a normalized PCR (Protein catabolic rate) • also need adequate calories (35 kcal/kg/day)
Phosphorus restrictions for dialysis patients
• Phosphorus 0.6 to 1.2 grams • limited to 1/2 cup milk per day • avoid colas in favor of lemon-lime or root beer • limit chocolate intake • take phosphate binders with each meal
2° Hyperparathyroidism
• Use phosphate binders to prevent or treat hyperphosphatemia • Oral or intravenous vitamin D analogs are used to suppress PTH and increase calcium levels • Monitor PTH on a quarterly basis, calcium and phosphorus monthly
