L23: Interorgan Amino Acid Metabolism

Question 1

LO1: Provide an explanation for why alanine and glutamine make up more than 50% of the AAs that are released from muscle (why is it more than can be accounted for by the AA composition of muscle protein?)

Answer 1

• alanine and glutamine are released by breakdown of BCAAs
• BCAAS can only be broken down in the muscle, as the BCAA transaminase (BCAT) is not present in the liver
• glutamine synthetase highly expressed in muscle as well, making it more likely that breakdown of AA will begin with donation of N to glutamate to produce glutamine (which is then converted to alanine)

Question 2

LO2: Describe the significance of alanine synthesis in muscle, its metabolic fate in liver, and name the major enzymes involved in the interorgan metabolism of alanine

Answer 2

• alanine (and glutamine) are key substrates for gluconeogenesis and ammoniagenesis in the liver and kidney
• after transamination in muscle, alanine is taken up by the liver and incorporated into urea/its carbon skeleton used for gluconeogenesis

ALT (alanine aminotransferase, reversible): converts glutamate and pyruvate to alpha-ketoglutarate and alanine

BCATm: transaminase that forms glutamate, which is converted to alanine (isozyme m expressed in most tissues, but not liver)

Question 3

LO3: Name the major metabolic fuel for intestinal cells and the products generated by this fuel

Answer 3

glutamine/glutamate=major fuel for the intestine

-generates alanine and citrulline as products

Question 4

LO4: Name the three BCAAs, describe the two common reactions that are involved in their catabolism, and list where they occur

Answer 4

BCAAs= valine, isoleucine, leucine= VIL

-transamination and decarboxylation occur in skeletal muscle, as there is little to no BCAT in the liver

Question 5

LO5: Compare and contrast BCKA DH with PDH and alpha-KG DH

Answer 5

BCKA DH vs. PDH vs. alpha-KG DH

• all are localized in the mitochondria
• all consist of three enzyme activities
• all require five coenzymes for catalytic activity
• E3 subunit is identical in all 3
• all release NADH and CO2
• like PDH, BCKA DH has a specific kinase and phosphatase associated with it that phos/dephosphorylates the E1 subunit
• TPP, lipoic acid, and FAD=prosthetic groups on BCKA DH and alpha-KG DH but are just cofactors for PDH

Question 6

LO6: Describe the reactions that are required to convert propionyl-CoA into succinyl-CoA and list the cofactors that are required for these interconversions

Answer 6

Propionyl-CoA generated by breakdown of the BCAAs Valine+Isoleucine

1. Propionyl-CoA carboxylase converts propionyl-CoA to D-methylmalonyl-CoA (requires biotin)
2. Epimerase converts D-methylmalonyl-CoA to L-methylmalonyl-CoA
3. Methylmalonyl-CoA mutase converts L-methylmalonyl-CoA to succinyl-CoA (requires Vit. B12)

Succinyl-CoA then used in TCA cycle

Question 7

LO7: Explain how a defect in propionyl-CoA utilization can lead to a carnitine deficiency, hypoglycemia, and hyperammonemia

Answer 7

• if propionyl-CoA isn’t properly utilized, it will bind to carnitine to generate acyl-carnitines which are excreted/can’t be used (ie propionic acidemia)
• hypoglycemia occurs because carnitine deficiency inhibits FA oxidation and blood glucose gets used faster to make up for; also, substrate for gluconeogenesis isn’t being created
• hyperammonemia occurs because CoA is getting tied up and isn’t available to make NAG (required to activate CPSI, which transfers an ammonia molecule from glutamine or glutamate to a molecule of bicarbonate)

Question 8

LO8: Describe the principal mechanism for regulation of BCAA metabolism

Answer 8

BCKA-DH COMPLEX ACTIVITY @ E1 CATALYZES THE RATE LIMITING STEP OF BCAA METABOLISM

Regulation by phoshorylation state:

• active when dephosphorylated (kinase inhibited by high levels of BCKAs, ie after a high protein meal)
• inactive when phosphorylated (kinase active when diet is free of protein, as BCAAs must be conserved)

Regulation by negative feedback inhibition:
-high levels of products (acyl-CoA, NADH) compared to substrate (CoA, NAD+) inhibit BCKA-DH

Question 9

LO9: Describe diets that might be useful in treating propionic acidemia and methylmalonic acidemia

Answer 9

PROPIONIC ACIDEMIA-deficiency of propionyl-CoA carboxylase

• diets high in carbs/medium chain FAs with frequent meals
• restricted protein intake
• enhance diet with biotin, Vit. B12, carnitine

METHYLMALONIC ACIDEMIA-deficiency of methylmalonyl-CoA mutase

• restricted protein intake/reduce BCAAs in diet
• enhance diet with biotin, Vit. B12, carnitine

Question 10

LO10: Provide an explanation for why some cases of methylmalonic aciduria can be treated with Vit B12 and others cannot

Answer 10

• if caused by Vit. B12 deficiency only, then supplementation can correct the deficiency
• inherited defect in methylmalonyl-CoA mutase enzyme is not corrected by Vit. B12 supplementation

Question 11

LO11: Name the defect in MSUD

Answer 11

-deficiency in BCKA-DH compex, so BCAAs cannot be catabolized