week 7- TCA cycle

functions of the TCA cycle- amphibolic pathway

involved in both the synthesis and degradation of biomolecules, a biosynthetic and degradative pathway, anaplerosis (build up, replenishing pathway) and cataplerosis (break down)

anaplerosis and cataplerosis roles in the TCA cycle

allow intermediates of the TCA cycle to enter and then leave to become precursors for the biosynthesis of other molecules that are important in metabolism

TCA cycle overview

starting point is acetyl-CoA (2C), condensation with OAA (4C) to citrate (6C), regeneration of OAA (6C); 2 NADHs produced and 2 CO2; 1 substrate-level phosphorylation; 1 FADH2

acetyl-CoA + OAA to citrate, catalyzed by citrate synthase

citrate is the starting point for FA synthesis, regulation: activated by OAA and ADP, inhibited by citrate, NADH, and ATP

isocitrate to alpha-ketoglutarate, catalyzed by isocitrate dehydrogenase

one of the rate-limiting steps, 1st of 3 NADH formed, 1st of CO2 released, regulation: allosterically activated by ADP binding reduces Km and Ca+, inhibited by high energy signals (ATP/NADH)

alpha-ketoglutarate to succinyl-CoA, catalyzed by alpha-ketoglutarate dehydrogenase complex

alpha-ketoglutarate dehydrogenase complex is similar to PDH but no phosphorylation control, require thiamine, lipoic acid, FAD, NAD, CoA, 2nd of 3rd NADH formed, 2nd CO2 released

alpha-ketoglutarate to succinyl-CoA regulation

allosterically activated by Ca+, inhibited by high energy signals (ATP/NADH), product inhibition (succinyl-CoA)

succinyl-CoA to succinate, catalyzed by succinate thiokinase

high energy theoester bond is cleaved to release the CoA group by alpha-ketoglutarate dehydrogenase complex, phosphorylation of GDP to GTP through energy released by the hydrolysis of the high energy bond, substrate-level phosphorylation

succinate to fumarate, catalyzed by succinate dehydrogenase

FAD reduced to FADH2, inner mitochondrial membrane (complex II)

malate to OAA, catalyzed by malate dehydrogenase

3rd NADH of cycle, regeneration of OAA, inhibited by citrate

rate of cycle is regulated to correspond to rate of ETC, hence the rate of ATP utilization

oxidation of acetyl-CoA in TCA cycle can only go as fast as e- from NADH/FADH2 are utilized by the ETC, ADP and NADH concentrations feed info on the rate of ATP utilization back to the TCA cycle, two important messengers: ATP:ADP and NADH:NAD+

TCA cycle- indicators of high energy state

ATP, NADH, Acetyl-CoA, citrate: INHIBIT

TCA cycle- indicators of low energy state

AMP, ADP, NAD+: STIMULATE