LEC 40 Amino Acid Metabolism Flashcards
Describe the basic principles of amino acid biosynthesis, including key synthetic pathways, enzymes, and co-factors. Describe the flow of nitrogen from proteins in peripheral tissues to the liver and through the urea cycle. Explain how amino acids are catabolized to glucogenic and ketogenic intermediates.
What’s the acronym for the 9 essential amino acids?
“PVT Tim Hall”
Phenylalanine
Valine
Threonine
Tryptophan
Isoleucine
Methionine
Histadine
Arginine* (only during +nitrogen balance)
Lysine
Leucine
What’s the difference b/w essential and nonessential amino acids?
essential amino acids must be obtain from the diet. nonessential can be synthesized
What enzyme converts b/w alpha-ketoglutarate and glutamate?
glutamate dehydrogenase
What enzyme directly converts glutamate to glutamine?
glutamine synthetase
What is the common required substrate for the enzymes glutamate dehydrogenase and glutamine synthetase?
NH4+
What is an important cofactor for transamination reactions?
Pyridoxal phosphate (B6)
What enzyme type catalyzes a transamination reaction?
aminotransferase
What are transamination reactions?
amine groups are transferred from one amino acid to the alpha-keto precursor of another
What enzyme catalyzes the reversible reaction of pyruvate & glutamate to form alanine & alpha-ketoglutarate?
alanine aminotransferase
Most transamination reactions involve which 2 compounds?
alpha-ketoglutarate and glutamate
What is coupled transamination?
transfer of amine groups b/w other amino acids is coupled to the glutamate/α-ketoglutarate reaction
What enzyme catalyzes the rxn b/w oxaloacetate/glutamate and aspartate/alpha-ketoglutarate?
aspartate aminotransferase
What enzyme converts glutamate to glutamic semialdehyde?
pyrroline-5-carboxylate synthetase
Glutamic semialdehyde can convert to which two compounds?
Ornithine & Pyrroline-5-carboxylate (to proline)
Pyrroline-5-carboxylate reductase converts pyrroline-5-carboxylate to which amino acid?
Proline
Ornithine and carbamoyl phosphate form citrulline using which enzyme?
ornithine transcarbamoylase
Citrulline and aspartate form argininosuccinate using which enzyme?
argininosuccinate synthetase
What enzyme converts argininosuccinate to fumarate and arginine?
argininosuccinate lyase
What enzyme forms carbamoyl phosphate?
carbamoyl phosphate synthetase I
What is carbamoyl phosphate’s purpose?
donates a carbamoyl group to citrulline
is also an entry point for nitrogen into the urea cycle
What cofactor is essential for the enzyme carbamoyl phosphate synthetase I that forms carbamoyl phosphate?
N-acetylglutamate
What enzyme catalyzes the rxn of aspartate & glutamine to form asparagine & glutamate?
asparagine synthetase (requires ATP)
Which amino acids are derived from 3-phosphoglycerate?
serine, cysteine, & glycine
Which amino acids are derived from Phosphoenolpyruvate and erythrose-4-phosphate?
tryptophan, tyrosine, & phenylalanine
Which amino acids are derived from pyruvate?
alanine, leucine, & valine
Which amino acids are derived from alpha-ketoglutarate?
glutamate, arginine, glutamine, proline, histidine (GAG PH)
What amino acids are derived from oxaloacetate?
aspartate, asparagine, lysine, methionine, threonine, isoleucine
What enzyme catalyzes the rxn of 3-phosphoglycerate to 3-phophopyruvate?
phosphoglycerate dehydrogenase
What is the key cofactor in the synthesis of glycine from serine?
Tetrahydrofolate (H4 folate)
What enzyme catalyzes the rxn b/w serine and glycine?
serine hydroxymethyltransferase
What enzyme converts homocysteine to methionine?
methionine synthase (methyl cycle)
What enzyme converts methionine to S-adenosylmethionine using ATP?
methionine adenosyltransferase
What enzyme converts homocysteine & serine to cystathionine?
cystathionine synthase
What enzyme converts cystathionine to cysteine?
cystathionase
What enzyme catalyzes the rxn of phenylalanine to tyrosine?
Phenylalanine hydroxylase
What is a key cofactor for hydroxylation of aromatic rings?
tetrahydrobiopterin
What disease occurs from a deficiency of phenylalanine hydroxylase?
Phenylketonuria (PKU) ~ Tyr deficient
What are the biochemical consequences of PKU?
- accumulation of phenylalanine and phenylpyruvate
- tyrosine deficiency
What is the fate of the Nitrogen in amino acids?
can be used for biosynthesis OR excreted in the urea cycle
What is the fate of the carbon skeletons of amino acids?
they turn into alpha-keto acids which can enter TCA and gluconeogenesis
What are the four key processes that characterize the overall flow of nitrogen during amino acid catabolism?
- transamination
- ammonia transport
- oxidative deamination of glutamate (glutamate dehydrogenase rxn)
- rxns of urea cycle
What is the most abundant circulating amino acid and a major carrier of nitrogen to the liver?
Glutamine
How is nitrogen transported from the peripheral tissues to the liver?
- NH4+, Mg-ATP, and L-glutamate react via Glutamine Synthase to form L-glutamine
- L-glutamine travels to the liver where it is converted back to L-Glutamate by glutaminase releasing NH4+
Describe the transport of nitrogen from the muscle to the liver by way of alanine.
Alanine Cycle:
1. Pyruvate (from glycolysis) in the muscle undergoes a transamination rxn and accepts an NH3 to form alanine
2. Alanine moves through the blood to the liver
3. Alanine is converted back to pyruvate in the liver releasing the nitrogen to the urea cycle
Describe the steps of the Urea Cycle.
- Carbamoyl phosphate is formed from HCO3-, NH4+ & ATP by carbamoyl phosphate synthetase I
- Ornithine & Carbamoyl phosphate form citrulline by ornithine transcarbamoylase
- citrulline & aspartate form argininosuccinate by argininosuccinate synthetase
- argininosuccinate forms fumarate and arginine by argininosuccinate lyase
- Arginine forms urea and regenerates ornithine by arginase
What part of the cell does the carbamoyl phosphate rxn and the ornithine transcarbamoylase rxn occur?
Mitochondria
The rest of the Urea Cycle occurs in the cytosol
After the formation of citrulline, the rest of the urea cycle occurs where in the cell?
Cytosol
What happens to glutamine once it enters the mitochondrial matrix?
glutaminase converts it into glutamate & NH4+
Amino acids react with alpha-ketoglutarate to form which compound that enters the mitochondria to deliver nitrogen?
glutamate
Alanine reacts with alpha-ketoglutarate to form which compound that enters the mitochondria to deliver nitrogen?
glutamate
Once inside the mitochondria, glutamate can undergo one of two rxns. What are these two reactions and enzymes involved?
- glutamate dehydrogenase converts it to alpha-ketoglutarate while releasing NH4+ for carbamoyl phosphate synthesis
OR
- glutamate reacts with oxaloacetate using aspartate aminotransferase to form alpha-ketoglutarate and aspartate (receives the nitrogen). the latter directly enters urea cycle
What are the biochemical consequences of carbamoyl phosphate synthetase and N-acetylglutamate synthetase deficiencies?
hyperammonemia due to lack of carbamoyl phosphate required by urea cycle
What are the biochemical consequences of ornithine transcarbamoylase deficiency?
hyperammonemia
increased orotic acid formed from excess carbamoyl phosphate
What are the biochemical consequences of argininosuccinate synthetase deficiency?
hyperammonemia
citrullinemia
arginine supplementation may be effective
What are the biochemical consequences of argininosuccinate lyase deficiency?
hyperammonemia
citrullinemia
increased argininosuccinate levels
arginine supplementation may be effective
What are the biochemical consequences of arginase deficiency?
Hyperammonemia*
Citrullinemia*
increased argininosuccinate levels*
increased arginine levels
*less severe than other urea cycle disorders
Which amino acids are strictly ketogenic?
Leucine and Lysine
Which 5 amino acids are converted to alpha-ketoglutarate?
- Arginine
- Histidine
- Proline
- Glutamate
- Glutamine
How is glutamate converted to alpha-ketoglutarate?
Deamination by glutamate dehydrogenase
OR
Transamination
How is glutamine converted to alpha-ketoglutarate?
- converted to glutamate by glutaminase
- deamination/transamination of glutamate
What common intermediate do arginine and proline both break down into in their path to alpha-ketoglutarate?
glutamic semialdehyde
Proline catabolism is the reverse of its synthesis and involves which enzyme?
proline oxidase
Which two amino acids are converted to oxaloacetate?
Asparagine & Aspartate
What enzyme converts asparagine to aspartate?
asparaginase
What enzyme converts aspartate to oxaloacetate?
aspartate transaminase (using pyruvate) –> forms alanine and oxaloacetate
Which 6 amino acids are converted to pyruvate?
Threonine
Glycine
Serine
Cysteine
Tryptophan
Alanine
How is alanine converted to pyruvate?
transamination (alanine aminotransferase) producing pyruvate and glutamate
How is serine converted to pyruvate?
serine dehydratase
How is glycine converted to pyruvate?
- converted to serine by serine hydroxymethyltransferase (tetrahydrofolate dependent)
- serine–>pyruvate (serine dehydratase)
What is the alternate path for glycine other than conversion to pyruvate?
can be cleaved to CO2 and NH4+ while producing an NADH by glycine cleavage enzyme
How is threonine converted to pyruvate?
- converted to 2-amino-3-ketobutyrate by threonine dehydrogenase
- 2-amino-3-ketobutyrate is converted to glycine and acetyl-CoA
- follows glycine steps to get to pyruvate
What is the other path that threonine can take besides converting to pyruvate?
- can convert to alpha-ketobutyrate by serine dehydratase
- alpha-ketobutyrate then converts to propionyl-CoA then to succinyl-CoA (into TCA)
Describe the catabolism of methionine to propionyl-CoA.
methionine is converted to homocysteine through the activated methyl cycle, then metabolized to propionyl-CoA; Homocysteine–(Cystathionine beta-synthase)–>Cystathionine–(Cystathionase)–>cysteine+alpha-ketobutyrate–>propionyl-CoA
Which amino acids are important sources of energy in muscle?
branched chain aminos (valine, isoleucine, leucine)
Valine is metabolized to _____, so valine is _______.
propionyl-CoA/succinyl-CoA; glucogenic
Isoleucine is metabolized to _____ & _____ making it both ______ & ______
propionyl-CoA & Acetyl-CoA; glucogenic & ketogenic
Leucine breaks down into ______ & ______, making it strictly _______.
Acetyl-CoA & Acetoacetate; ketogenic
What is maple syrup urine disease and its biochemical consequences?
branched chain ketoacid dehydrogenase deficiency resulting in accumulation and excretion of branched chain alpha-keto acids and related metabolites
What do phenylalanine and tyrosine break down into?
fumarate (glucogenic) and acetoacetyl-CoA (ketogenic)
What enzyme is deficient in Tyrosinemia Type I?
Fumarylacetoacetase
What are the biochemical consequences of Tyrosinemia type I?
Fumarylacetoacetate Hydrolase Deficiency:
-tyrosinemia
-accumulation of fumarylacetoacetate & maleylacetoacetate and their derivatives succinyl acetone and succinyl acetoacetone
-succinyl acetone inhibits porphobilinogen synthase (aminolevulinic acid dehydratase)
-acute hepatic porphyria and accumulation of amino levulinic acid
What enzyme is deficient in tyrosinemia type II?
Tyrosine aminotransferase
What are the biochemical consequences of tyrosinemia type II?
Tyrosine Aminotransferase Deficiency:
-tyrosinemia
-elevated tyrosine metabolites
What enzyme is deficient in tyrosinemia type III?
Hydroxyphenylpyruvate Dioxygenase
What are the biochemical consequences of tyrosinemia type III?
Hydroxyphenylpyruvate Dioxygenase Deficiency:
-tyrosinemia
-elevated tyrosine metabolites
(same as tyrosinemia type II)
What enzyme is deficient in Alkaptonuria?
Homogentisate-1,2-Dioxygenase
What are the biochemical consequences of alkaptonuria?
-tyrosinemia
-elevated homogentisate levels
Tryptophan is metabolized to _____ & _____, so tryptophan is both ________ & ________.
pyruvate & acetyl-CoA; glucogenic & ketogenic
Lysine is metabolized entirely to _______, so lysine is strictly ________.
acetyl-CoA; ketogenic
