MCAT - Biochem - Glycolysis, Gluconeogenesis, and Pentose Phosphate Pathway

Cori Cycle

acidic lactic acid formed from fermentation in blood cells are delivered back to the liver to be converted to glucose for red blood cell use

1,3-BPG and PEP (1,3-Bisphosphoglycerate and posphoenolpyruvate)

high energy intermediates used to generate ATP by substrate level phosphorylation

starch

how plants store glucose branched

fructose-1,6-bisphosphatase

in the cytoplasm, reverse of PFK1 removes phosphate fructose-1,6-bisphosphate --> fuctose 6-phosphate, rate limiting step of gluconeogenesis, activated by ATP directly and glucagon indirectly, inhibited by AMP and fructose-2,6-bp directly and insulin indirectly

adaptations to high altitude (low pO₂)

increased respiration, O2 affinity, rate of glycolysis, 2,3-BPG in RBC, # hemoglobin, all normalize blood O2 levels

phosphoenolpyruvate carboxykinase (PEPCK)

induced by glucagon and cortisol occurs in cytoplasm converts: oxaloacetate +GTP --> PEP

malate

intermediate conversion of oxaloacetate which can leave mitochondria via malate-aspartate shuttle, oxidized to OAA in cytoplasm

pentose phosphate pathway (PPP)

irreversible metabolic process in the cytoplasm of cells purpose: produces NADPH and ribose 5-phosphate for nucleotide synthesis activated by insulin and NADP⁺ inhibited by NADPH part 1: irreversible: glucose 6-phosphate → ribulose 5-phosphate + NADPH uses glucose-6-phosphate dehyrdogenase (G6PD) part 2: reversible: ribose 5-phosphate → pool of sugars

Glycolysis 5

isomerase, DHAP > glyceraldehyde 3-P (DHAP can be shuttled to liver to be turned into glycerol 3-P for fat storage)

metabolism of galactose

lactose → galactose + glucose by lactase lactose hydrolyzed to galactose and glucose by lactase in duodenum > transported to liver via hepatic portal vein where phosphorylated by galactokinase to trap in cell > converted to glucose 1-phosphate by galactose-1-phosphate uridyl transferase

Glut 2

low affinity transporter on hepatocyts and pancreatic cells, captures glucose in hepatic vein after meals primarily for storage, km 15mM, glucose sensor (in beta-islet cells serves as glucose sensor for insulin release along with glucokinase) specific glucose transporter that allows glucose to leave the liver cell

storing glucose

muscles store excess glucose as glycogen liver converts glucose into fatty acids for storage via glycolysis adipose tissue requires glucose to form DHAP which is converted to glycerol phosphate to store incoming fatty acids as triacylglycerols

substrate level phosphorylation

not dependent on oxygen, only means of ATP production in anaerobic tissue

fate of NADH

of O2 present, oxidized in electron transport chain, if O2 absent, oxidized by lactate dehydrogenase

pyruvate kinase

phosphoenolpyruvate --> pyruvate, produces ATP activated by fructose 1,6-bisphosphate (feedforward activation)

Glycolysis 2

phosphoglucose isomerase, glucose 6-P > fructose 6-P

Glycolysis 7

phosphoglycerate kinase, bisphosphoglycerate + Pi > 3-phosphoglycerate, ADP > ATP

Glycolysis 8

phosphoglycerate mutase, 3-phosphoglycerate > 2-phosphoglycerate

irreversible steps in glycolysis

pyruvate glucokinase/hexokinase, PFK-1, pyruvate kinase ("How Glycolysis Pushed Forward the Process: Kinases")

glycogen synthase

rate limiting enzyme of glycogenesis, activated by insulin in liver and muscle activated by glucose-6-phosphate inhibited by epinephrine inhibited by glucagon (which phosphorylates and inactivates enzyme)

glycogen phosphorylase

rate limiting enzyme of glycogenolysis breaks bonds using Pi activated by glucagon in liver activated by epinephrine and AMP in muscles inhibited by ATP

glucose-6-phosphate dehydrogenase (G6PD)

rate-limiting enzyme of the Pentose Phosphate Pathway, activated by NADP+ and insulin and inhibited by NADPH (ribose phosphate building block of nucleic acids)

glutathione

reducing agents that can help reverse free radical formation before damage done to cells

Gluconeogenesis

reverse of glycolysis, occurs during fasting occurs in the cytoplasm and mitochondria, predominantly in the liver, promoted by epinephrine and glucagon, inhibited by insulin (used to raise blood glucose levels after glycogen used up 24 hours after fasting)

glycogen

storage form of glucose branched polymer of glucose degraded in liver and skeletal muscle

metabolism of fructose (sucrose)

sucrose → glucose + fructose using sucrase sucrose hydrolyzed by sucrase resulting in fructose and glucose > transported via hepatic portal vein and phosphorylated by fructokinase > fructose 1-phosphate cleaved by aldolase B into glyceraldehyde and DHAP

PDH cofactors

thiamine, pyrophosphate, lipoic acid, CoA, FAD and NAD+

pyruvate dehydrogenase (PDH)

transition step pyruvate→acetyl-CoA complex of enzymes that converts pyruvate to acetyl-CoA, stimulated by insulin and inhibited by acetl-CoA

Glut 4

transporter of glucose in adipose and muscle tissue, responds to glucose concentrations in peripheral blood, km of 5mM close to normal blood glucose levels, insulin stimulates movement of these transports to membrane via exocytosis mechanism (ie if insulin increases, GLUT 4 transporters on plama membrane increases)

galactokinase

traps galactose by adding phosphorus

DHAP (dihydroxyacetone phosphate)

used in hepatic and adipose tissue, formed from fructose 1,6-bisphosphate, isomerized to glycerol 3-phosphate then converted to glycerol to store incoming fatty acids as triacylglycerides

Red blood cells (erythrocytes) anerobic glycolysis

1 glucose =2 ATP 1,3-BPG → 2,3-BPG using bisphosphoglycerate mutase

3-phosphoglycerate kinase

1,3 bisphosphoglycerate --> 3-phosphoglycerate, generates ATP in substrate level phosphorylation

three fates of pyruvate

1. converted to acetyl-CoA by PDH (pyruvate dehydrogenase). insulin causes increase 2. lactate by lactate dehydrogenase, 3. converted to oxaloacetate by pyruvate carboxylase if too much acetyl-CoA (ie enter gluconeogenesis)

isoform

A slightly different version of the same protein, often specific to a given tissue ex: different isoforms of gycogen enzymes in muscles and liver

kinase

An enzyme that transfers phosphate ions from one molecule to another (from ATP)

4 glucose transporters

GLUT 1 GLUT 2 GLUT 3 GLUT 4 (GLUT 2 and 4 are located in specific cells and are highly regulated)

cell respiration net count

GLYCOLYSIS: 1 glucose→2 pyruvate in cytoplasm used 2ATP made 4ATP + 2NADH NET: 2 ATP + 2 NADH TRANSITION STEP: 2 pyruvate → 2 Acetyl-CoA used 2 NAD⁺ made 2NADH + 2 Acetyl-CoA + 2CO₂ NET: 2 NADH + 2CO₂ KREB CYCLE: in mitochondrial matrix (repeat twice due to 2 pyruvates) 2 Acetyl CoA + 4C→ 6C 6C + NAD⁺ → 5C + NADH + CO₂ 5C + NAD⁺ → 4C + NADH + CO₂ 4C + ADP → 4C + ATP 4C + NAD⁺ + FADH → 4C (rearrange) + NADH + FADH₂ NET: 2 FADH₂ + 6 NADH + 4 CO₂ + 2 ATP total made entering ETC: 4ATP + 6CO₂ +10NADH + 2FADH₂ ETC: in inner membrane of mitchondria (1 NADH=2.5 ATP, 1 FADH₂=1.5 ATP) 3 complexes pumps out H into intermembrane space protons pump back to matrix through ATP synthase makes 32 ATP 6 O₂ + H⁺ → 6 H₂O

glycolysis

Glucose → 2 pyruvate 2 ATP 2 NADH cytoplasmic pathway that converts one glucose into two pyruvates releasing energy captured in two substrate level phosphorylations, produces 2 ATP, and 2 NADH used in aerobic respiration pathway (does not occur in red blood cells, or other cells deprived of mitochondria or oxygen)

NADPH vs NADH

NADH: where NAD⁺ is electron acceptor, oxidizing agent, oxidizes other molecules, is reduced to NADH NADPH: electron donor, reducing agent, reduces other molecules and is oxidized

Glycolysis 3

PFK-1, fructose 6-P > fructose 1,6-Bis P, ATP > ADP

pyruvate carboxylase

activated by acetyl-CoA. too much acetyl-CoA produced from glycolysis causes negative feedback to pyruvate production. causes gluconeogenesis oxaloacetate (from citric acid cycle) can't leave mitochondria. convert oxoloacetate to malate, which can leave via malate-aspiratate shuttle mitochondrial enzyme activated by (1st step to bypass pyruvate kinase in gluconeogenesis)

fructose 2,6-bisphosphate

activates PFK-1, involved in the indirect activation and inhibition of PFK-1 for metabolites of glycolysis to be fed to glycogen, fatty acids, and other storage molecules, not just ATP production

hexose monophosphate shunt (HMP)

aka PPP, occurs in cytoplasm of most cells, generates NADPH and sugars for biosynthesis (derived from ribulose 5-phosphate)

Glycolysis 4

aldolase, fructose 1,6-Bis P > glyceraldehyde 3-P + DHAP (dihydroxyacetone phosphate)

glucogenic amino acids

all except leucine and lysine, can be converted into intermediated that feed into gluconeogenesis

gluconeogenesis avoiding irreversible steps in glycolysis

avoid glucokinase, PFK1 and pyruvate kinase by using: pyruvate carboxylase + PEPCK fructose-1,6-bp glucose-6-phosphatase

2,3-bisphosphoglycerate (2,3-BPG)

binds allosterically to beta-chains of hemoglobin and decreases O2 affinity, shifts dissociation curve left allowing for O2 unloading, doesn't bind to fetal hemoglobin

glycogen

branched polymer of glucose, stored in cytoplasm as granules with a protein core, branching allows greater density at periphery stored in liver for the maintenance of blood glucose levels, stored in muscles as energy reserve

glycogenolysis

breakdown of glycogen uses glycogen phosphorylase to break a-1,4 bonds and a debranching enzyme to break a-1,6 bonds

debranching enzyme

breaks a-1,6 bonds to release glucose from glycogen two enzyme complex, moves a block of oligoglucose from one branch and connects it to the chain using alpha-1,4 glucosidic links, removes branchpoint connected with alpha-1,6 glycosidic links, freeing a glucose molecule

ketogenic amino acids

can be converted into ketone bodies which can be used as an alternate fuel

Gluconeogenesis key intermediates

cannot convert aetyl-CoA to glucose convert 3 intermediates to pyruvate: 1. lactate using lactate dehydrogenase 2. alanine using alanine aminotransferase 3. glycerol 3P using glycerol-3P dehydrogenase to DHAP

insulin

causes an abundance of glucose to enter a cell and be shunted to glycolysis, aerobic respiration, fuel storage pathways

Beriberi

characterized by congestive heart failure or nerve damage, can be a result of thiamine deficiency

Wernicke-Korsakoff syndrome

characterized by difficulty walking, uncoordinated eye movements, confusion, memory disturbances, can be a result of thiamine deficiency

processes in mitochondria

citric acid cycle ETC oxidative phosphorylation beta oxidation (fatty acid metabolism)

aldolase B

cleaves fructose-1,6 bisphosphate to form glyceraldehyde and DHAP

fructose

comes from honey, fruit , and sucrose, trapped in cell by fructokinase

branching enzyme

converts a-1,4 branch to a-1,6 branch introduces alpha-1,6 glycosidic linkages into the granule as it grows, (hydrolyzes alpha-1,4 bonds to release a block of oligoglucose and binds it at a different location,"1-6 puts a branch in the mix")

aldose reductase

converts galactose --> galactitol in lens of eye

pyruvate carboxylase + PEP

converts pyruvate to PEP and avoids irreversible pyruvate kinase in glycolysis

yeast fermentation

converts pyruvate to ethanol and carbon dioxide and NAD⁺ 3C→2C + CO₂

glycogenin

core protein within glycogen granule

sucrase

duodenal brushborder enzyme

Glycolysis 9

enolase, 2-phosphoglycerate > PEP

lactate dehydrogenase

enzyme for fermentation oxidizes NADH to NAD+, replenishing the oxidized coenzyme for glyceraldehyde-3-phosphate dehydrogenase.

glucose-6-phosphatase

enzyme found in endoplasmic reticulum of liver cells, glucose 6-phosphate→ glucose GLUT transporter brings glucose back to cytoplasm uses ATP energy from B-oxidation reverse of glucokinase/hexokinase

bisphosphoglycerate mutase

enzyme located on hemoglobin that catalyzes 1,3 BPG -->2,3-BPG

epimerase

enzymes that catalyze the conversion of one sugar epimer to another (these epimers are different at exactly 1 chiral carbon)

galactose-1-phosphate uridyl transferase

epimerase, converts galactose 1-phosphate to glucose 1-phosphate (in hepatic cells)

fructokinase

fructose --> fructose 1-phosphate

phosphofructokinase-1 (PFK-1)

fuctose 6-phosphate --> fructose 1,6-bisphosphate using ATP, rate limiting enzyme, inhibited by ATP and citrate, activated by AMP (citrate intermediate in citric acid cycle, both it and ATP signal that there is enough energy present)

phosphofructokinase-2 (PFK-2)

fuctose 6-phosphate --> fructose 2,6-bisphosphate, found mostly in the liver, activated by insulin, inhibited by glucagon

other monossaccharide metabolism

galactose and fructose

glycogen storage disease

genetic deficiencies that affect glycogen metabolism enzymes are defective which can lead to accumulation or lack of glycogen

galactosemia

genetic deficiency of galactokinase or galactose-1-phosphate uridultransferase which results in cataracts from excess conversion to galactitol by aldose reductase

Glycolysis 1

glucokinase / hexokinase, glucose > glucose 6-P, ATP >ADP,

glucokinase

glucose --> glucose 6-phosphate, present in pancreatic Beta-islet cells as part of glucose sensor, phosphorylation prevent glucose from exiting via GLUT transporter, induced by insulin in hepatocytes

hexokinase

glucose --> glucose 6-phosphate, in peripheral tissues, low Km value for max velocity at low [glucose], inhibited by glucose 6-phosphate

Glycolysis 6

glyceraldehyde 3-P dehydrogenase, glyceraldehyde 3-P + Pi> 1,3-Bisphosphoglycerate, NAD+ > NADH + H

glyceraldehyde-3-phosphate dehydrogenase

glyceraldehyde 3-phosphate --> 1,3 bisphosphoglycerate, uses Pi, produces NADH which feeds into elctron transport chain

von Gierke's disease

glycogen storage disease resulting from a defect in glucose 6-phosphatase cannot finish gluconeogenesis person has low blood sugar between meals needs continuous feeding to maintain blood sugar buildup of glucose-6P leads to enlarged and damaged liver

Glycogenesis

glycogen synthesis: glucose → glucose-6-P glucose-6-P → glucose-1-P glucose-1-P + UTP → glucose + UDP glucose + UDP → glycogen (glycogenin) + UDP using glycogen synthase, branching enzyme

rate limiting enzymes

glycolysis: PFK1 fermentation: lactate dehydrogenase glycogenesis: glycogen synthase glycogenolysis: glycogen phosphorylase gluconeogenesis: fructose-1,6-bp pentose phosphate pathway: glucose-6-phosphate dehydrogenase

fermentation

without oxygen produces NAD⁺ converts pyruvate to lactate Process by which cells release energy in the absence of oxygen and oxidize NADH to NAD+ (reducing pyruvate to lactate in mammals, to ethanol in yeast)