Intertissue Relationships in the Metabolism of Amino Acids

• The body maintains a large free amino acid pool in the blood, even during fasting, allowing tissues continuous access to these building blocks.
• Amino acids are used for gluconeogenesis by the liver, as a fuel source for the gut, and as neurotransmitter precursors in the nervous system. They are also required by all organs for protein synthesis.
• During an overnight fast and during hypercatabolic states, degradation of labile protein (primarily from skeletal muscle) is the major source of free amino acids.
• The liver is the major site of urea synthesis. Nitrogen from other tissues travels to the liver in the form of glutamine and alanine.
• Branched-chain amino acids are oxidized primarily in the skeletal muscle.
• Glutamine in the blood serves a number of roles:
  • The kidney utilizes the ammonium ion carried by glutamine for excretion in the urine to act as a buffer against acidotic conditions.
  • The kidney and the gut utilize glutamine as a fuel source.
  • All tissues utilize glutamine for protein synthesis.
• The body can enter a catabolic state characterized by negative nitrogen balance under the following conditions:
  • Sepsis (any of various pathogenic organisms or their toxins in the blood or tissues)
  • Trauma
  • Injury
  • Burns
• The negative nitrogen balance results from increased net protein degradation in skeletal muscle, brought about by release of glucocorticoids. The released amino acids are used for protein synthesis and cell division in cells involved in the immune response and wound healing.

Purine and Pyrimidine Metabolism

• Purine and pyrimidine nucleotides can both be synthesized from scratch (de novo) or salvaged from existing bases.
• De novo purine synthesis is complex, requiring 11 steps and 6 molecules of adenosine triphosphate for every purine synthesized. Purines are initially synthesized in the ribonucleotide form.
• The precursors for de novo purine synthesis are glycine, ribose 5-phosphate, glutamine, aspartate, carbon dioxide, and N¹⁰-formyltetrahydrofolate.
• The initial purine ribonucleotide synthesized is inosine monophosphate. Adenosine monophosphate and guanosine monophosphate are each derived from inosine monophosphate.
• Since de novo purine synthesis requires a large amount of energy, purine nucleotide salvage pathways exist such that free purine bases can be converted to nucleotides.
• Mutations in purine salvage enzymes are associated with severe diseases, such as Lesch-Nyhan syndrome and severe combined immunodeficiency disease.
• Pyrimidine bases are initially synthesized as the free base and then converted to nucleotides.
• Aspartate and cytoplasmic carbamoyl phosphate are the precursors for pyrimidine ring synthesis.
• The initial pyrimidine nucleotide synthesized is orotate monophosphate, which is converted to uridine monophosphate. The other pyrimidine nucleotides will be derived from a uracil-containing intermediate.
• Deoxyribonucleotides are derived by reduction of ribonucleotides, as catalyzed by ribonucleotide reductase. The regulation of ribonucleotide reductase is complex.
• Degradation of purine containing nucleotides results in uric acid production, which is eliminated in the urine. Elevated uric acid levels in the blood lead to gout.

Tetrahydrofolate, Vitamin B12, and S-Adenosylmethionine

• One-carbon groups at lower oxidation states than carbon dioxide (which is carried by biotin) are transferred by reactions involving tetrahydrofolate, vitamin B₁₂, and S-adenosyl methionine.
• Tetrahydrofolate is produced from the vitamin folate and obtains one-carbon units from serine, glycine, histidine, formaldehyde, and formic acid.
• The carbon attached to tetrahydrofolate can be oxidized or reduced, thus producing a number of different forms of tetrahydrofolate. However, once a carbon has been reduced to the methyl level, it cannot be reoxidized.
• The carbons attached to tetrahydrofolate are known collectively as the one-carbon pool.
• The carbons carried by folate are used in a limited number of biochemical reactions but are very important in forming deoxythymidine monophosphate and the purine rings.
• Vitamin B₁₂ participates in two reactions in the body: conversion of L-methylmalonyl coenzyme A to succinyl coenzyme A and the conversion of homocysteine to methionine.
• S-adenosyl methionine, formed from adenosine triphosphate and methionine, transfers the methyl group to precursors forming a variety of methylated compounds.
• Both vitamin B₁₂ and methyl tetrahydrofolate are required in methionine metabolism; a deficiency of vitamin B₁₂ leads to overproduction and trapping of folate in the methyl form, leading to a functional folate deficiency. Such deficiencies can lead to
  • Megaloblastic anemia
  • Neural tube defects in newborn

Synthesis and Degradation of Amino Acids and Amino Acid Derived Products

• Humans can synthesize only 11 of the 20 amino acids required for protein synthesis; the other 9 are considered essential amino acids for the diet.
• Amino acid metabolism to a large extent utilizes the cofactors pyridoxal phosphate, tetrahydrobiopterin, and tetrahydrofolate.
  • Pyridoxal phosphate is primarily required for transamination reactions.
  • Tetrahydrobiopterin is required for ring hydroxylation reactions.
  • Tetrahydrofolate is required for one-carbon metabolism (discussed further in Chapter 33).
• The nonessential amino acids can be synthesized from glycolytic intermediates (serine, glycine, cysteine and pyruvate), tricarboxylic acid cycle intermediates (aspartate, asparagine, glutamate, glutamine, proline, arginine, and ornithine), or from existing amino acids (tyrosine from phenylalanine).
• When amino acids are degraded, the nitrogen is converted to urea, and the carbon skeletons are classified as either glucogenic (a precursor of glucose) or ketogenic (a precursor of ketone bodies).
• Defects in amino acid degradation pathways can lead to disease.
  • Glycine degradation can lead to oxalate production, which may lead to one class of kidney stone formation.
  • Defects in methionine degradation can lead to hyper homocysteinemia, which has been linked to blood clotting disorders and heart disease.
  • A defect in branched-chain amino acid degradation leads to maple syrup urine disease, which has severe neurological consequences.
  • Defects in phenylalanine and tyrosine degradation lead to phenylketonuria, alcaptonuria, and albinism.
• Amino acids are also the precursors for the small nitrogen-containing neurotransmitters, such as the catecholamines, serotonin, and histamine.
• Glycine is required for the biosynthesis of heme. Mutations in enzymes involved in heme biosynthesis give rise to a class of diseases known as the porphyrias.

Fate of Amino Acid Nitrogen: Urea Cycle

• Amino acid catabolism will generate urea, a nontoxic carrier of nitrogen atoms.
• Urea synthesis occurs in the liver. The amino acids alanine and glutamine will carry amino acid nitrogen from peripheral tissues to the liver.
• Key enzymes involved in nitrogen disposal are transaminases, glutamate dehydrogenase, and glutaminase.
• The urea cycle consists of four steps and incorporates a nitrogen from ammonia and one from aspartate into urea.
• Disorders of the urea cycle lead to hyperammonemia, a condition toxic to the nervous system, health, and development.