Glycolysis pt 3

Anaerobic glycolysis (fermentation)

Generation of energy (ATP) without consuming oxygen or NAD⁺; regenerates NAD⁺ for further glycolysis; no net change in oxidation state of the sugars

Lactic acid fermentation

Reduction of pyruvate to lactate by lactate dehydrogenase under hypoxic/anaerobic conditions; regenerates NAD⁺; ΔG'° = −25.1 kJ/mol

Lactate dehydrogenase

Enzyme that reversibly converts pyruvate → L-lactate using NADH + H⁺, regenerating NAD⁺; key enzyme in lactic acid fermentation

Why does lactate build up during exercise?

During strenuous exercise (<1 min), pyruvate is reduced to lactate faster than it can enter aerobic pathways; acidification of muscle eventually prevents continued strenuous contraction

The Cori Cycle

Metabolic cycle in which muscle produces lactate (via glycolysis), releases it into blood, liver takes it up and converts it back to glucose (gluconeogenesis), which returns to muscle via blood

Ethanol fermentation

Two-step irreversible reduction of pyruvate to ethanol in yeast: (1) pyruvate decarboxylase removes CO₂ to form acetaldehyde; (2) alcohol dehydrogenase reduces acetaldehyde to ethanol using NADH

Pyruvate decarboxylase

Enzyme in yeast that converts pyruvate → acetaldehyde + CO₂; requires cofactors Mg²⁺ and thiamine pyrophosphate (TPP)

Alcohol dehydrogenase

Enzyme that converts acetaldehyde → ethanol using NADH + H⁺; requires Zn²⁺ and NAD⁺; present in humans (for ethanol metabolism) but humans lack pyruvate decarboxylase

Role of CO₂ in ethanol fermentation

CO₂ produced by pyruvate decarboxylase causes carbonation in beer and makes bread dough rise

Thiamine pyrophosphate (TPP)

Coenzyme derived from vitamin B1; acts as an acetaldehyde carrier in the thiazolium ring; used by pyruvate decarboxylase, pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and transketolase

Gluconeogenesis

Metabolic pathway that synthesizes glucose from non-carbohydrate precursors (pyruvate, lactate, oxaloacetate, glucogenic amino acids, glycerol); occurs mainly in the liver

Why can't mammals convert fatty acids to glucose?

Fatty acid degradation produces acetyl-CoA, which cannot be converted to oxaloacetate for net glucose synthesis (no net conversion of acetyl-CoA → oxaloacetate in animals)

Gluconeogenesis precursors in animals

Pyruvate, lactate, oxaloacetate, glucogenic amino acids (convertible to citric acid cycle intermediates), and glycerol from triacylglycerols

Glycolysis vs. gluconeogenesis: shared steps

Most steps are reversible and used by both pathways in opposite directions; only the three irreversible steps of glycolysis must be bypassed in gluconeogenesis

Three irreversible glycolysis steps bypassed in gluconeogenesis

(1) Hexokinase → bypassed by glucose 6-phosphatase; (2) Phosphofructokinase-1 → bypassed by fructose 1,6-bisphosphatase; (3) Pyruvate kinase → bypassed by pyruvate carboxylase + PEP carboxykinase

Pyruvate carboxylase

Enzyme that converts pyruvate + HCO₃⁻ → oxaloacetate using ATP and biotin cofactor; first bypass step converting pyruvate to PEP in gluconeogenesis; located in mitochondria

PEP carboxykinase (PEPCK)

Enzyme that converts oxaloacetate + GTP → phosphoenolpyruvate (PEP) + CO₂ + GDP; second bypass step in gluconeogenesis; can operate in mitochondria or cytosol

Biotin

CO₂ carrier cofactor; attached to pyruvate carboxylase via a long biotinyl-Lys tether that swings CO₂ from site 1 (carboxylation) to site 2 (carboxylation of pyruvate); required for the first gluconeogenesis bypass

Fructose 1,6-bisphosphatase

Gluconeogenesis enzyme that hydrolyzes fructose 1,6-bisphosphate → fructose 6-phosphate + Pᵢ; bypasses PFK-1; coordinately/oppositely regulated with PFK-1 to prevent futile cycling

Glucose 6-phosphatase

Gluconeogenesis enzyme that hydrolyzes glucose 6-phosphate → glucose + Pᵢ; bypasses hexokinase; present mainly in liver, allowing glucose export to blood

Energy cost of gluconeogenesis

4 ATP + 2 GTP + 2 NADH per glucose synthesized from 2 pyruvate; more expensive than glycolysis but physiologically necessary

Why is gluconeogenesis necessary?

Brain, nervous system, and red blood cells rely almost exclusively on glucose for ATP; when glycogen stores are depleted (starvation, vigorous exercise), gluconeogenesis provides glucose

Glucogenic amino acids

Amino acids whose carbon skeletons can be converted to pyruvate or citric acid cycle intermediates for net glucose synthesis; all 20 except leucine and lysine are glucogenic

Pentose phosphate pathway (PPP)

Metabolic pathway that converts glucose 6-phosphate to NADPH and ribose 5-phosphate; has an oxidative phase (generates NADPH and R-5-P) and a non-oxidative phase (interconverts sugar phosphates)

NADPH (in PPP context)

Main electron donor product of the oxidative phase of PPP; used for reductive biosynthesis (fatty acids, steroids) and repair of oxidative damage (via glutathione reductase)

Ribose 5-phosphate

5-carbon sugar product of the oxidative phase of PPP; biosynthetic precursor for nucleotides (DNA, RNA synthesis) and some coenzymes

Oxidative phase of PPP

Converts glucose 6-phosphate → 6-phosphogluconate → ribulose 5-phosphate → ribose 5-phosphate; produces 2 NADPH and 1 CO₂; catalyzed by G6PD, lactonase, and 6-phosphogluconate dehydrogenase

Non-oxidative phase of PPP

Interconverts ribose 5-phosphate back to glucose 6-phosphate (and glycolytic intermediates) using transketolase and transaldolase; used when more NADPH than R-5-P is needed (e.g., liver, adipose)

Glucose 6-phosphate dehydrogenase (G6PD)

First enzyme of the oxidative PPP; converts G-6-P → 6-phosphogluconolactone, generating NADPH; regulated by NADPH (product inhibition); deficiency causes susceptibility to oxidative stress

G6PD deficiency

Genetic condition impairing PPP; cells cannot produce enough NADPH to combat oxidative stress; can be fatal with certain drugs, herbicides, or foods; carriers have resistance to malaria due to high oxidative stress in infected RBCs

NADPH regulation of PPP vs. glycolysis

High NADPH inhibits G6PD, directing glucose 6-phosphate into glycolysis; low NADPH activates G6PD, pushing more flux into the pentose phosphate pathway

Fates of pyruvate

Under aerobic conditions → acetyl-CoA → citric acid cycle; under anaerobic/hypoxic conditions → lactate (animals, some microbes) or → ethanol + CO₂ (yeast)

Why glycolysis occurs mainly in muscle and brain

These tissues have high, rapid ATP demands and rely on glycolysis; they lack the full gluconeogenic enzyme set (e.g., glucose 6-phosphatase)

Why gluconeogenesis occurs mainly in the liver

Liver expresses all bypass enzymes including glucose 6-phosphatase, allowing it to export free glucose into the blood for use by other tissues