| INHERITED DISEASES OF AMINO ACID METABOLISM
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| page 256 |  | | page 257 |
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Table 18-4.
Origins of non-essential amino acids (i.e. those not required in a normal diet). |
| Body_ID: None |
Origins of nonessential amino acids |
| Body_ID: T018004.50 |
| Amino acid | Source in metabolism, etc. |
| Body_ID: T018004.100 |
| alanine | from pyruvate via transamination |
| Body_ID: T018004.150 |
| aspartic acid, asparagine, arginine, glutamic acid, glutamine, proline | from intermediates in the citric acid cycle |
| Body_ID: T018004.200 |
| serine | from 3-phosphoglycerate (glycolysis) |
| Body_ID: T018004.250 |
| glycine | from serine |
| Body_ID: T018004.300 |
| cysteine* | from serine; requires sulfur derived from methionine |
| Body_ID: T018004.350 |
| tyrosine* | derived from phenylalanine via hydroxylation |
| Body_ID: T018004.400 |
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| Body_ID: T018004.450 |
*These are examples of nonessential amino acids that depend on adequate amounts of an essential amino acid.
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Table 18-5.
Essential amino acids (i.e. those required in the diet). |
| Body_ID: None |
| Essential amino acids |
| Body_ID: T018005.50 |
| Mnemonic | Amino acid* | Notes or comments |
| Body_ID: T018005.100 |
| P | phenylalanine | required in the diet also as a precursor of tyrosine |
| Body_ID: T018005.150 |
| V | valine | one of three branched-chain amino acids |
| Body_ID: T018005.200 |
| T | threonine | metabolized like a branched-chain amino acid |
| Body_ID: T018005.250 |
| T | tryptophan | its complex heterocyclic side chain can not be synthesized in humans |
| Body_ID: T018005.300 |
| I | isoleucine | one of three branched-chain amino acids |
| Body_ID: T018005.350 |
| M | methionine | provides the sulfur for cysteine and participates as a methyl donor in metabolism; the homocysteine is recycled |
| Body_ID: T018005.400 |
| H | histidine | its heterocyclic side chain cannot be synthesized in humans |
| Body_ID: T018005.450 |
| A | arginine | whereas arginine can be derived from ornithine in the urea cycle in amounts sufficient to support the needs of adults, growing animals require it in the diet |
| Body_ID: T018005.500 |
| L | leucine | a pure ketogenic amino acid |
| Body_ID: T018005.550 |
| L | lysine | neither of the nitrogens of lysine can undergo transamination |
| Body_ID: T018005.600 |
*The mnemonic PVT TIM HALL is useful for recalling the names of the essential amino acids.
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| In addition to deficiencies in the urea cycle, specific defects in the metabolism of the carbon skeletons of various amino acids were among the first disease states to be associated with simple inheritance patterns. These observations gave rise to the concept of the genetic basis of inherited metabolic disease states, also known as 'inborn errors of metabolism'. Garrod considered a number of disease states that appeared to be inherited in a Mendelian pattern, and proposed a correlation
between these abnormalities and specific genes, in which the disease state could be either dominant or recessive. Dozens of inborn errors of metabolism have now been described, and the molecular defect has been described for many of them. Three classical inborn errors of metabolism will be discussed in some detail here.
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| METHYLMALONYL-COA MUTASE DEFICIENCY (Incidence 1 in 30 000) |
| A 4-day-old child became increasingly drowsy and developed tachypnoea. Blood gas analysis demonstrated acidosis. Urine demonstrated gross ketonuria and plasma ammonia was raised at 250 μmol/l (normal range in a term infant of up to 100 μmol/L). The ammonia continued to rise over the following 12 hours to 350 μmol/L. |
| Comment. This is an emergency situation. The ammonia will cause cerebral edema and brain damage. With the acidosis being present, the most likely defects are in propionyl-CoA carboxylase, methylmalonyl-CoA mutase or holocarboxylase, the enzyme that conjugates biotin to carboxylase enzymes. The appropriate treatment is to stop protein (nitrogen) intake and provide adequate carbohydrates; large doses of bicarbonate and fluids; carnitine to help renal excretion of CoA metabolites, releasing CoA for intermediary metabolism; and biotin which may work on propionic acidaemia and will certainly improve holocarboxylase deficiency. Vitamin B12 may also stimulate mutase activity. This child's organic acid profile demonstrated gross elevation of methylmalonate and methylcitrate confirming methylmalonic acidaemia. The hyperammonemia is thought to result from inhibition of carbamoyl phosphate synthetase I by short chain fatty acids and CoA esters, possibly indirectly by inhibiting the synthesis of the allosteric effector, N-acetyl-glutamate. |
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