Pyruvate Dehydrogenase + TCA B&B Flashcards
what enzymes are required to funnel pyruvate into gluconeogenesis vs TCA?
pyruvate carboxylase —> gluconeogenesis
pyruvate dehydrogenase complex —> acetyl CoA —> TCA
what 5 cofactors are required for the pyruvate dehydrogenase complex, which converts pyruvate into acetyl-CoA for entry into TCA cycle? from what are they each derived?
- NAD+ - synthesized from niacin/B3
- FAD+ - synthesized from riboflavin/B2
- Coenzyme A (CoA) - synthesized from pantothenic acid/ B5
- thiamine (vit B1)
- Lipoic acid
for what 4 metabolic enzymes is thiamine (vit B1) a cofactor?
thiamine = vit. B1, converted to thiamine pyrophosphate (TPP)
- pyruvate dehydrogenase
- alpha-ketaglutarate dehydrogenase (TCA)
- alpha-ketoacidosis dehydrogenase (branched chain amino acids)
- transketolase (HMP shunt)
what occurs from thiamine deficiency and which 2 syndromes are classically associated with it?
thiamine (vit. B1) is cofactor for pyruvate dehydrogenase - with out it, acetyl CoA is not made for entry into TCA cycle —> ATP depletion, esp. effecting tissues with a lot of aerobic metabolism (nerves/heart)
- Beriberi: underdeveloped areas, dry type (polyneuritis, muscle weakness) or wet type (tachycardia, high-output HF, edema)
- Wernicke-Korsakoff syndrome: alcoholics (malnourished, poor vitamin absorption), confusion
Beriberi and Wernicke-Korsakoff syndrome are similar in that they are both caused by a deficiency in…
thiamine (vit. B1) - cofactor for pyruvate dehydrogenase - with out it, acetyl CoA is not made for entry into TCA cycle —> ATP depletion, esp. effecting tissues with a lot of aerobic metabolism (nerves/heart)
Beriberi - underdeveloped countries
Wernicke-Korsakoff - alcoholics
what causes beriberi? how does the dry type differ from the wet type?
thiamine (vit. B1) deficiency - cofactor for pyruvate dehydrogenase - with out it, acetyl CoA is not made for entry into TCA cycle —> ATP depletion, esp. effecting tissues with a lot of aerobic metabolism (nerves/heart)
dry type - polyneuritis (nerve pain), muscle weakness
wet type - tachycardia, high-output HF, edema
(Beriberi occurs in underdeveloped areas)
the following are all similar in that they all require which vitamin as a cofactor?
1. pyruvate dehydrogenase
2. alpha-ketaglutarate dehydrogenase (TCA)
3. alpha-ketoacidosis dehydrogenase (branched chain amino acids)
4. transketolase (HMP shunt)
thiamine, aka vitamin B1
why should thiamine be given to malnourished patients before glucose?
thiamine (vit. B1) is cofactor for pyruvate dehydrogenase (converts pyruvate to acetyl coA for TCA)
without it, glucose can’t be broken down to make ATP via TCA cycle - Wernicke-Korsakoff syndrome (confusion, confabulation due to malnourishment) could worsen following glucose administration
where do we get NAD+?
NAD+ is synthesized from niacin (vit. B3)
niacin can be from diet or synthesized from tryptophan
from what vitamins are the following cofactors derived?
a. niacin (NAD)
b. pantothenic acid (CoA)
c. thiamine
d. riboflavin (FAD)
thiamine - B1
riboflavin (FAD) - B2
niacin (NAD) - B3
pantothenic acid (CoA) - B5
The Rabbit Never Pauses
[rabbit is another word for Bunny, as in B vitamins]
what is the mechanism by which arsenic inhibits the pyruvate dehydrogenase complex? how does arsenic poisoning present?
arsenic binds/inhibits lipoic acid, one of the cofactors for PDH
oxidized to arsenous oxide, giving off garlic breath odor
non-specific symptoms - vomiting, diarrhea, coma, death
what are the respective effects of PDH kinase vs PDH phosphatase on pyruvate dehydrogenase?
PDH kinase —> INACTIVATION
PDH phosphatase —> activation
cheat code: remember phosphorylation turns OFF glycolysis pathway enzymes (glucagon, epi cause phosphorylation via PKA)… PDH follows glycolysis (on the way to TCA), so it makes sense that phosphorylation would shut it down
how does PDH (pyruvate dehydrogenase) complex deficiency present? how should it be treated?
often XLR (males), pyruvate shunted to alanine (—> alanine cycle) or lactate (—> cori cycle)
—> infant with poor feeding/growth, labs show high alanine + lactic acidosis
—> treat with keto diet - low carbs reduces lactic acidosis, high fats converted to acetyl CoA (bypass need for PDH), ketogenic amino acids (lysine, leucine)
[form of mitochondrial disorders]
An infant is presenting with poor feeding and growth. Labs reveal elevated alanine and lactic acidosis. What is going on and which 2 amino acids should be emphasized in their diet as treatment?
PDH complex deficiency: form of mitochondrial disorder, pyruvate shunted to alanine (—> alanine cycle) or lactate (—> cori cycle)
—> treat with keto diet - low carbs reduces lactic acidosis, high fats converted to acetyl CoA (bypass need for PDH), ketogenic amino acids (lysine, leucine) drive ketone over glucose production
in the fasting state, citrate levels decrease because pyruvate is diverted to become ______ (TCA substrate), which then becomes glucose,
and acetyl CoA from _____ is diverted to become ketone bodies
in the fasting state, citrate levels decrease because pyruvate is diverted to become OXALOACETATE. which then becomes glucose
and acetyl CoA from FATTY ACIDS is diverted to become ketone bodies
[recall oxaloacetate combines with acetyl CoA via citrate synthase to become citrate in TCA cycle]
