Topic 4: TCA Cycle Flashcards
What does sodium fluoroacetate do to the TCA Cycle?
It binds with OAA to make Fluorocitrate which in turn irreversibly binds to the ACONITASE enzyme at Step 2.
will see Apprehension, restless, wandering, circling seizures, straining to urinate and defecate, Hyperthermia, vomiting, vocalization, rapid rigor mortis
What are cofactors of PDH?
NAD+, CoA, Mg++, Thiamine-PP, Lipoic Acid, FAD
What vitamins are necessary for PDH?
Thiamine/B1 (for Thiamine-PP), Riboflavin/B2 (for FAD), Niacin/B3 (for NAD), Pantothenic Acid/B5 (for CoA)
What’s unique about enzymatic reactions yiedling CO2?
They are energetically irreverisble.
What steps of the TCA Cycle yield CO2?
Step 3) Isocitrate dehydrogenase
Step 4) Alph-ketoglutarate dehydrogenase
How is PDH turned off?
PDH Kinase with phosphorylate it turning it OFF.
Activated by ATP, Acetyl CoA, NADH (it can tell that PDH has made enough products for the time being)
Deactivated by ADP, CoA-SH, pyruvate, NAD+ (it can tell PDH has work to do)
How is PDH turned
PDH Phosphatase will take of phosphate turning it ON.
Activated by Insulin and epinephrine/adrenaline
What are some PDH Poisons?
ARSENITE (from Arsenic) screws with disulfide bond on lipoic acid, thereby screwing with anything that uses it, hence PDH.
MERCURY does the same thing.
They ALSO INHIBIT a-KDH at Step 4 in TCA Cycle.
What inihibits PDH?
NADH and Acetyl CoA are feedback inhibitors. (Dual action of inhibiting PDH while activating PDH Kinase to deactivate the enzyme entirely)
What is Step 1 of TCA Cycle?
Oxaloacetate with Acetyl CoA via Citrate Synthase makes Citrate
Yields CoA-SH and uses H2O.
Inhibited by ATP, Citrate, Fatty Acyl CoA
What is Step 2 of TCA Cycle?
Citrate via Aconitase makes Isocitrate
Inhibited by Fluoroacetate
What is Step 3 of TCA Cycle?
IsoCitrate via isocitrate dehydrogenase makes alpha-ketoglutarate
Yields NADH and CO2
Inhibited by ATP and NADH
What is Step 4 of TCA Cycle?
alpha-ketoglutarate via Alpha-ketoglutarate dehydrogenase makes Succinyl-CoA
Yields NADH and CO2.
Requires Thiamine. Anaplerotic potential
Inhibited by ATP, NADH, Succinyl-CoA, As, and Hg
What is Step 5 of TCA Cycle?
Succinyl-CoA via Succinate Thiokinase makes Succinate.
Yields ATP/GTP and CoA-SH. Uses H20.
What is Step 6 of TCA Cycle?
Succinate via succinate dehydrogenase makes Fumarate.
Yields FADH2.
This is the enzyme that is the same as Complex 2 in ETC.
Inhibited by OAA. (Malonate too but not normally present in the body, experimentally administered in the past to study TCA Cycle)
What is Step 7 of TCA Cycle?
Fumarate via fumarase makes Malate.
Uses H2O.
What is Step 8 of the TCA Cycle?
Malate via Malate dehydrogenase makes Oxaloacetate.
Yields NADH. Only enzyme that can work both ways going from OAA to Malate if need be.
What are the 5 major outcomes of the TCA Cycle?
1) Major source of carbon dioxide in the body
2) Major source of NADH and FADH2
3) Conversion of excess energy and intermediates to synthesis of glucose and fatty acids
4) Provides precursors for proteins and nucleic acids
5) Its components control directly or indirectly other enzyme systems
What intermediates have anaplerotic potential?
Oxaloacetate, alpha-ketoglutarate, Succinyl-CoA (different from Succinate, don’t mix them up), Fumarate
What is the rate limiting concentration of the TCA Cycle?
Oxaloacetate.
How is TCA Cycle primarily regulated?
Availability of: Oxaloacetate, Acetyl CoA, NAD+, FAD, ADP/GDP, Pi
Also linked to ETC. If the ETC is screwed then so is the TCA Cycle. ATP/ADP Ratio and availability of O2.
What would you expect to see in a PDH Deficiency?
elevated Lactate, Pyruvate and Alanine.
Leads to chronic lactic acidosis.
Severe neurological deficits
What would you expect to see with Fumarase deficiency?
Encephalopathy and dystonia (abnormal muscle tone).
Abnormal amounts of fumarate in urine.
Autosomal recessive gene.
What would you expect to see with a Succinate-DH deficiency?
encephalopathy
What is Milk Sickness (aka sick stomach, puking illness, trembles, slows) caused by?
Tremetol, which is a compound found in snakeroot and rayless goldenrod.
Inhibits CITRATE SYNTHASE – Step 1 of TCA Cycle.
Fat soluble and concentrates in milk. Neonates super susceptible
What would you expect to see from Milk Sickness/Tremetol toxicity?
KETOACIDOSIS – muscle damage with pain and weakness, ataxia, stiff gait, trembling, constipation, vomiting, salivation, tremors, hepatic necrosis, death
