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L7 TCA Cycle (TCA Cycle
Tri-carboxylic acid, Citric acid, Krebs cycle
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L7 TCA Cycle
TCA Cycle
- Tri-carboxylic acid, Citric acid, Krebs cycle
- Sir Hans Krebs 1937
- Occurs in the presence of O2 (has to have O2 for the TCA cycle to work)
- Located in mitochond (compartments in the mitochond)
- Acts as the final common pathway for oxidation of CH2O, lipids & prots (via Acetyl-CoA) (catabolic)
- Plays major role in glucogenesis, transamination, deamination and lipogenesis (anabolic) - later lecture
- ∴ amphibolic
- Produces reducing equivalents (NADH & FADH2) tht enter respiratory chain → ATP [ L9 ]
Mitochondrion
- Pyruvate passively enters mitochond & before the TCA cycle, oxidation of pyruvate to acetyl-CoA & NADH (must be converted to aceCoA before entering the TCA cycle)
- Acetyl-CoA then combines w/ 4C oxaloacetate & CoA is released
- The 6 carbons from 2 pyruvates oxidised to CO2
- NADH, FADH2 & ATP produces
- Oxaloacetate is reformed
Steps
- 4C Oxaloacetate + 2C Acetyl CoA -6C citrate
- Citrate converted to isocitrate (move OH grp). Aconitase reqs Fe2+
- Oxidative decarboxylation of isocitrate to α-ketoglutarate. Release of first CO2 & generation of first NADH. Isocitrate DH is rate-limiting ezm & tightly controlled
- Oxidative decarboxylation of 𝞪-ketoglutarate DH another multi ezm complex (similar to PDH) reqs coenz: TPP, lipoic acid, FAD, NAD+, CoA. Releases CO2 & second
- Succinyl CoA converted to succinate, release of GTP (substrate lvl phosphorylation). Enz succinyl CoA synthatase AKA succinate thiokinase
- Succinate oxidised to fumarate, generates FADH2. Succinate DH is embedded in inner mitoch membrane
- FUmarate is hydrated to form malate- fumarase also called fumarate hydratase
- Malate to oxaloacetate, final NADH generated. Endergonic, but citrate synthase pulls reaction in direction of OAA
TCA Cycle Overview
- Net 1 turn of cycle= 3 NADH, 1 GTP, 1 FADH2, releases 2 CO2
-
Clinical Perspective
- Liver only tissue in which all metabolic processes occur significantly- profound effect during liver damage (hepatitis, cirrhosis)
- TCA v few genetic abnormalities- incompatible w/ life
- Fumarase deficiency- fumarate → malate
~ Autosomal rec disorder
~ Severe neurological impairment, encephalopathy, dystonia [twith: can't control muscle mvt]
- TCA is aerobic process, anoxia or hypoxia leads total or partial inhibition of cycle
- Four soluble B vit have precise roles TCA cycle- Riboflavin (FAD), Niacin (NAD), Thiamine (𝜶-KG- DH) & Panthothenic acid (Coezm A)
Pyruvate Dehydrogenase *
- Complex of 3 ezms, physically linked to enable correct seq of reactions, w/o release of intermediates, each has spec coezms [each subunit has a coezm]
- E1 = Thiamine pyrophosphate (TPP)
- E2 = lipoic acid (acyl lipollysine) & CoA
- E3 = FAD & NAD+
- Pyruvate + CoA + NAD+ → CO2 + NADH + acetyl-CoA
- ATP might inhibit the ezm
- NADH might inhibit the prod of the ezm, & the substrate of the nxt ezm
Regulation- PDH
- Highly regulated to respond to E charge in (C)
- ATP = ⤒ E lvl
- AMP = ⤓ E lvl
- the E charge = important way for the (C) to know what to activate & inactivate
~ ↑ vl of NADH= reduce acti. of ezm
~ ↑E charge= lots of ATP= turn off the activity, reduce ct of PDH
Reg
- Also subject to cov modification by PDH kinase & PDH phosphatase
- 3 subunits: needs to be dephosphorylated by ezm phosphatase to be activated
- ↑lvls of pyruvate= stop it frm being phosphorylated & pyruvate ⇈ in its activity
- ↑lvls NADH = activate PDH
- having a Pgrp @ spec site makes it inactive
Clinical Perspective
- Tissues w/ little or no mitochond depend on glycolysis for ATP- pyruvate can't enter TCA cycle
~ RBC, cornea, lens, retina, kidney medulla, testic, leukocytes & white muscle
- PDH deficiency (usually E1 ⇒ lactic acidosis ⇒) neurological defects & death, but can be managed in some instances by low CH2O diet (ketogenic- ↑fat & prot)
- Lactate formation - later lecture
Energy
Importance of NADH & FADH2
- Main products of Glycolysis & TCA cycle = NADH & FADH2
- Process tht utilises these e- carriers to produce ATP = Oxidative Phosphorylation
- Occurs via Electron Transport Chain
- E- transferred from NADH & FADH2 to O2 to drive the formation of ATP
~ NADH ⇒ 3ATP
~ FADH2 ⇒ 2ATP
Glucose (C6 H12 O6) catabolism E Yield
- Glycolysis:
2 ATP (net)
2 NADH (2 x 2ATP)
- Pyruvate to acetyl CoA
2 NADH (2 x 3ATP)
2 Acetyl CoA ⇒
- TCA Cycle
⇒ 3 NADH (3 x 3ATP)
⇒1 FADH2 (2ATP)
⇒ 1 GTP
Glycogen
- Glycogen → Glucose = Glycogenolysis
- Glycogen phosphorylase regulation?
Arsenic poisoning
- Inhbition of Glycolysis (arsenate)
- & TCA cycle (main reason it's toxic)
- ARsenite (trivalent arsenic)- binds to lipoic acid SH grp forming a stable complex (unable to bind to ezms: PDH & 𝜶-ketoglutarate DH -coezm)
- Causes a spontaneous conversion = don't get ATP
Glycolysis
- ...occurs in cytosol
- The next 2 steps of respiration in mitochond: Pyruvate oxidation then TCA cycle
- Conversion of pyruvate to acetyl CoA is NOT part of the TCA cycle [need it to further catabolise]
- Pyruvate = 3C, Acetyl CoA = 2C ∴ lose 1C of CO2
Acetyl CoA
- Pivotal molec in metabolism (acetyl intermediate)
- DRAW pyruvate & acetyl grp
- presence of high E thioester grp on aceCoA
Acetyl-CoA Formation
- The oxidation (oxidative decarboxylation) of Pyruvate to Acetyl-CoA is the irreversible route from Glycolysis to TCA cycle (can't use the carbons in the acetyl CoA to make pyruvate from Glycolysis to TCA Cycle - (mitochond)
- Catalysed by sev diff ezms working sequentially in a multi-ezm complex
= Pyruvate dehydrogenase PDH
- 5 rxns catabolised
- Yellow= substrates, Pink = products
Learning Outcomes
- Understand the reaction catalysed by PDH & its regulation
- Describe the reactions of the TCA cycle, where they occur within the (C) & the reg of the cycle
- Know st of pyruvate & acetyl grp of Acetyl-CoA
- Understand E yield of glucose catabolism
- Know the pathway of glycogen breakdown
- Appreciate the action of arsenic as a poison