Overview Function generation of ATP from glucose via substrate-level phosphorylation (as opposed to oxidative phosphorylation) used by all cells with O2 pyruvate enters citric acid cycle (after being created in glycolysis) NAD+ regenerated via oxidative phosphorylation without O2 pyruvate cannot enter citric acid cycle after glycolysis NAD+ must be regenerated via conversion of pyruvate to lactate catalyzed by lactate dehydrogenase only source of energy for RBCs generation of intermediates for other pathways 1,3-BPG intermediate of glycolysis can be converted to 2,3-DPG modifies the hemoglobin-O2 binding curve binds HbA and ↓ binding affinity of O2 a compensatory mechanism for ↓pO2 Pathway in cytoplasm irreversible net reaction glucose + 2Pi + 2 ADP + 2 NAD+ → 2 pyruvate + 2 ATP + 2 NADH + 2H+ + 2 H2O Important enzymes hexokinase - converts glucose into glucose-6-phosphate allowing "trapping" inside cell distribution widely present in most body tissues allows trapping of glucose at all blood glucose levels kinetics high affinity → low Km low capacity → low Vmax regulation feedback inhibited by glucose-6-phosphate glucokinase (hexokinase IV) distribution liver β cells of pancreas uses as a means to measure blood glucose and release insulin accordingly mutated in the monogenenic, autosomal dominant form of diabetes called Maturity Onset Diabetes of the Young type 2 (MODY2) kinetics low affinity → high Km high capacity → high Vmax regulation induced by insulin (to store glucose in liver after a meal) no direct feedback inhibition phosphofructokinase-1 rate-limiting step inhibited by ATP, citrate stimulated by AMP, fructose-2,6-bisphosphate fructose 2,6-bisphosphate synthesized by phosphofructokinase-2 pyruvate kinase catalyzes substrate-level phosphorylation inhibited by ATP, alanine activated by fructose-1,6-bisphosphate Hormonal regulation fasting state ↑ glucagon → ↑ cAMP → ↑ protein kinase A → ↑ FBPase-2, ↓ PFK-2 fed state ↑ insulin → ↓ cAMP → ↓ protein kinase A → ↓ FBPase-2, ↑ PFK-2 Disorders of Glycolysis Pyruvate kinase deficiency AR (most commonly) pathophysiology ↓ ATP generation inability to maintain Na+/K+ ATPase leads to RBC swelling RBC lysis back up of glycolysis ↑ 2,3-BPG and other glycolytic intermediates presentation chronic hemolysis ↓ O2 affinity for HbA due to ↑ 2,3-BPG no Heinz bodies unlike glucose 6-phosphate dehydrogenase deficiency