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Amino Acid Metabolism

Jamal Ross BSc, Mbbs

Main role of prots= functional and structural. No storage form unlike carbs and fats.
Negative nitrogen balance- Excreted nitrogen >intake. Post-op, cancer, tuberculosis

Positive nitrogen balance intake of nitrogen>excreted. E.g growth, pregnancy

In constant dynamic steady state.

Essential AAs

Ile, Leu , Val, Lys, Thr ,Tryp, Met, Phe, His , Arg

I Leuked vaguely Lyke His Arnt Phelicia Thought Trevor Mcdonald

His-> Needed for infant growth.

Digestion of large polypeptides occurs mainly in small intestines. Proteolytic enzymes break down into dipeptides and amino acids. Proteolytic enzymes show different specificity. E.g an amino-peptidase to take off the amino group and a carboxy peptidase etc. Transpoted across SI membrane by 5 different transporters; 1. Neutral 2. Basic 3. Imino 4. Acidic 5. Beta

-Glutamyl Cycle

Proteasome

Proteins tagged selectively for degradation with or sometimes without ubiquitination.

The proteasome core complex, with a 20S sedimentation coefficient, contains 28 subunits.

Most proteases are synthesised as a larger polypeptide and then activated later by post-processing.

20 S Proteasome (yeast) closed state

two views
PDB 1JD2

Amino Acid pool

Deamination- The first step

Transamination - exchange of the alpha amino group between one alpha amino acid and another alpha keto acid Prosthetic group=

pyridoxal phosphate (PLP)/ der of vit B6

1. First step of catabolism

2. Synthesis of Non-essential AAs

3. Interconversion of Amino Acids

Lysine, threonine and proline are not

transaminated. They follow direct degradative pathways.

Oxidative deamination - of glutamate is the final reaction which removes the amino group.

Glutamate Dehydrogenase catalyzes a major reaction that effects net removal of N from the amino acid. It can use NAD+ or NADP+ as H+ acceptor. Oxidation at the -carbon is followed by hydrolysis, releasing NH4+. This occurs mainly in the kidney where the NH4+ excretion is required for acidbase regulation

Nonoxidative demaination
The enzymes are dehydratases which act on hydroxyl amino acids, for example Serine. And trans-sulphuration reaction removes ammonia from Cysteine. Histidine also undergoes nonoxidative deamination which is catalyzed by histidase.

Being highly toxic, ammonia should be eliminated or detoxified, as and when it is formed. Even very minute quantity of ammonia may produce toxicity in central nervous system. The ammonia must be transported via non-toxic pathway and is immediately detoxified into urea.

in the brain

in the kidney

Alanine-Glucose cycle

Urea Cycle

Total of 5 reactions in urea cycle

The first 2 take place in the mitochondria and the last 3 are in the cytosol. Reaction 1: Carbamoyl Phosphate Synthetase - I (CPS- I ) catalyzes this reaction. Ammonia is the N input. The reaction, which involves cleavage of 2 ~P bonds of ATP, is essentially irreversible.

CPS-1 is the rate limiting enzyme in the urea cycle.

Reaction 2

The enzyme is ornithine carbamoyl transferase, OCT. This reaction is irreversible.

+ Reaction 3

In this way aspartate contributes the second nitrogen atom to urea. Production of arginino-succinate catalyzed by arginino-succinate synthetase (ASS) is an energetically expensive process, since the ATP is split to AMP and pyrophosphate. The pyrophosphate is then cleaved to inorganic phosphate using pyrophosphatase, so the overall reaction costs two ~P.

+ Reaction 4

Elimination of fumarate from arginino-succinate then yields arginine. arginino-succinate lyase (ASL) catalyzes this reaction.

+ Reaction 5

Cleavage of arginine by arginase to produce urea regenerates ornithine, which is then available for another round of the cycle.

Overview urea cycle

Hepatic coma*
1. High [NH3] would drive Glutamine Synthase: glutamate + ATP + NH3 glutamine + ADP + Pi
This would deplete glutamate a neurotransmitter & precursor for synthesis of the neurotransmitter GABA.

2. . Depletion of glutamate & high ammonia level would drive Glutamate Dehydrogenase reaction to reverse: glutamate + NAD(P)+ a-ketoglutarate + NAD(P)H + NH4+ The resulting depletion of a-ketoglutarate, an essential Krebs Cycle intermediate, could impair energy metabolism in the brain.

Treatment in urea cycle enzyme deficiencies.

1. Limiting protein intake

2. Liver transplant

Carbon skeletons
Amino acids, when deaminated, yield -keto acids, that directly or via additional reactions, feed into major metabolic pathways.
1. synthesis of non-essential amino acid. 2. go further into Krebs cycle to yield energy. 3. to synthesis glucose or lipid.

Glucogenic Ketogenic. Glucogenic

and Ketogenic

AA classification*

Glucogenic: Gly, Ser, Val, His, Arg, Cys, Pro, Ala, Glu, Gln, Asp, Asn, Met
Ketogenic: Leu and Lys Keith leuses Lyse Glucogenic & Ketogenic: Ile, Trp, Tyr, Phe, Thr Phelicia (took) Three Trips (to the) Tyre Ile

One-Carbon Metabolism

one-carbon groups are carried by tetrahydro folic acid (THFA). THFA is produced from folic acid. During the catabolism of amino acid, some functional group contained only one molecule of carbon element will be got, which are called one-carbon Main sources of one carbon units: Serine, Glycine, Histidine and Tryptophan

One carbon reactions

+ AA

Individual AAs
Metabolism
Glucogenic

Goes into.
Haem, creatinine, Purines, Gluthathione

Status
Non-essential

Glycine

Alanine Threonine

Glucogenic Glucogenic

Glycolysis, krebs, gluconeogenesis Non-oxidative deamination -> ketobutyric acid Deaminated to pyruvate, 1-carbon donor, form other AA Formation of glutathione, AA transport, coenzyme, PAPS sulfuration reactions Forms SAM in methionine cycle

Non-essential Essential

Serine

Glucogenic

Non-essential

Cysteine (sulphur containing

Glucogenic

non-essential

Met Cysteine (sulphur containing

Glucogenic

Essential

Branched Chain Amino Acids

Branched chain amino acids are Valine, Leucine and Isoleucine. They are all essential amino acids. They are initially share in part a common pathway.
Branched Chain -Keto Acid Dehydrogenase (BCKDH) is a multi-subunit complex homologous to Pyruvate Dehydrogenase complex. Genetic deficiency of BCKDH is called Maple Syrup Urine Disease (MSUD). High concentrations of branched chain - keto acids in urine give it a characteristic odor.

H3C H3C S H2 H2 H C C C COO

H2 H2 H C C C

COO

CH2 O

NH3+ Adenine H H OH

methionine

NH3+

ATP PPi + Pi
H

H OH

S-adenosylmethionine (SAM) acceptor methylated acceptor

THF N5-methyl-THF adenosine H2O

HS H2 H2 H C C C COO S CH2 O H H OH H H OH

H2 H2 H C C C

COO

NH3+ Adenine

homocysteine

NH3+

S-adenosylhomocysteine