BGM1002 Biochemistry - Protein and alcohol metabolism PDF

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Protein and alcohol metabolism: Amino acid degradation: 

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The first call for amino acids that are released on protein degradation or turnover (balance between synthesis and degradation) is for use as building blocks for biosynthetic reactions (anabolism). Any not needed as building blocks are degraded to compounds able to enter the metabolic mainstream. o The amino group is first removed (deamination/transamination). o The remaining carbon skeleton is metabolised to glucose, one of several citric acid cycle intermediaries, or acetyl CoA. The major site of amino acid degradation in mammals is the liver, although muscles readily degrade the branched chain amino acids (Leu, Ile, Val). The fate of the α-amino group will be considered first, followed by that of the carbon skeleton.

Alpha-amino groups are converted into ammonium ions by the oxidative deamination of glutamate:   

The α-amino group of many amino acids is transferred to α-ketoglutarate to form glutamate, which is then oxidatively deaminated to yield ammonium ion (NH₄⁺). Aminotransferases (transaminases) catalyse the transfer of an α-amino group from an α-amino acid to an α-ketoacid. These enzymes generally funnel α-amino groups from a variety of amino acids to αketoglutarate for conversion into NH₄⁺.

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As a result, a different amino acid and a different ketoacid are formed. E.g. aspartate aminotransferase catalyses the transfer of the amino group of aspartate to α-ketoglutarate: o Aspartate + α-ketoglutarate  oxaloacetate + glutamate

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E.g. alanine aminotransferase catalyses the transfer of the amino group of alanine to α-ketoglutarate: o Alanine + α-ketoglutarate  pyruvate + glutamate

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Transamination reactions are reversible.

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The nitrogen atom in glutamate is converted into free ammonium ion by oxidative deamination, a reaction catalysed by glutamate dehydrogenase. o This enzyme can utilise either NAD⁺ or NADP⁺ (in some species).

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The sum of the reactions catalysed by aminotransferases and glutamate dehydrogenase is:

α-amino acid + NAD⁺ (or NADP⁺) + H₂O > α-ketoacid + NH₄⁺ + NADH (or NADPH) + H⁺ 

In most organisms, NH₄⁺ is converted into urea, which is excreted.

Carbon atoms of degraded amino acids emerge as major metabolic intermediates:

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The strategy of amino acid degradation is to transform the carbon skeletons into major metabolic intermediates that can be converted into glucose or oxidised by the CAC.

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The carbon skeletons of all 20 fundamental amino acids are only converted into 7 molecules: 1. Pyruvate 2. Acetyl CoA 3. Acetoacetyl CoA 4. α-ketoglutarate 5. Succinyl CoA 6. Fumarate 7. Oxaloacetate

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Amino acids that are degraded to acetyl CoA and acetoacetyl CoA are termed ketogenic amino acids because they can give rise to ketone bodies or fatty acids.

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Amino acids that are degraded to any of the other options are called glucogenic amino acids as they can be converted into glucose.

Ethanol metabolism leads to an excess of NADH – 

Ethanol cannot be excreted and must be metabolised in a two-step oxidation process.  The first step, catalysed by alcohol dehydrogenase, takes place in the cell cytoplasm: o Ethanol + NAD⁺  acetaldehyde + NADH + H⁺ CH₃CH₂OH CH₃CHO  The second step, catalysed by aldehyde dehydrogenase, takes place in the mitochondria: o Acetaldehyde + NAD⁺ + H₂O  acetate + NADH + H⁺ CH₃CHO CH₃COO⁻  Note that ethanol consumption leads to an accumulation of NADH.  This high concentration of NADH inhibits gluconeogenesis by preventing the oxidation of lactate to pyruvate (it tricks the body into thinking the CAC is full).  The consequences may be hypoglycaemia and lactic acidosis.  The overabundance of NADH also inhibits fatty acid oxidation. o An important metabolic purpose of fatty acid oxidation is to generate NADH for ATP generation by oxidative phosphorylation. o An alcohol consumer’s NADH needs are met by ethanol metabolism. o The excess NADH actually signals that the conditions are right (i.e. CAC is full) for fatty acid synthesis (the resultant accumulation of acetyl CoA is funnelled into the lipogenesis pathway). o Triacylglycerols therefore accumulate in the liver and a condition called ‘fatty liver (steatosis)’ is developed.  When people have an alcohol intolerance, they cannot produce either alcohol dehydrogenase or aldehyde dehydrogenase (or maybe both). o This essentially poisons the consumer and induces flushing, sweating, nausea, rapid heart rate, liver damage, etc. o Drugs used to treat alcoholism purposely induce these effects by noncompetitively binding to aldehyde dehydrogenase. o This defect is very common in people with Asian genetics....