In the realm of biochemistry, ‘metabolism’ comprises two distinct sets of pathways: anabolism, or synthesis; and catabolism, or break down. In humans, twenty amino acids serve as the building blocks of all proteins. Amino acids consist of a central carbon bonded to an NH2 group (the amino terminus); a COO- group (the carboxyl terminus); and a variable ligand called a side chain.
Although amino acids can be categorized a number of ways, most scientists focus on the properties of their side chains. The aliphatic amino acids include alanine, glycine, leucine, isoleucine, proline, and valine. They have relatively hydrophobic, chemically inert side chains. Three amino acids are commonly phosphorylated on their -OH groups: serine, threonine, and tyrosine (also an aromatic amino acid). Two contain sulfur – cysteine and methionine. Two amino acids contain non-reactive aromatic side chains – phenylalanine and tryptophan. The acidic amino acids are glutamate and aspartate; their amine derivatives are glutamine and asparagine. Amino acids with basic side chains include histidine, arginine, and lysine.
Since amino acid catabolism in humans is arguably more complicated than anabolism, it will be discussed first. Amino acids present a special challenge for the human body. Unlike carbohydrates and lipids, they are not stored for later use. Amino acids must be used for protein synthesis, broken down for energy, or, in some cases, be converted to other useful molecules, for instance, neurotransmitters.
The definitive step in amino acid catabolism involves the removal of the nitrogen containing amine group, a process called deamination. Since humans cannot dispose of nitrogen as ammonia due to its extreme toxicity, ammonia enters the urea cycle where liver cells conjugate it into urea. The bloodstream carries urea to the kidneys, which excrete it into the urine.
The remainder of the amino acid is referred to as a carbon skeleton, which biochemists classify as glucogenic or ketogenic. Glucogenic amino acids undergo a series of enzymatic reactions which converts them to pyruvate or into intermediates of the Krebs cycle. These intermediate compounds are ultimately turned into glucose by a process called gluconeogenesis. Eighteen of the twenty amino acids are partially or entirely glucogenic.
Ketogenic amino acids give rise to a group of molecules called ketone bodies, specifically acetoacetate and beta hydroxybutyrate. Ketone bodies are converted by the liver and kidneys into a two carbon unit called acetyl CoA, as opposed to pyruvate. Consequently, their carbon skeletons cannot be converted to glucose because human cells cannot convert acetyl CoA into pyruvate. The only purely ketogenic amino acids are leucine and lysine. Five amino acids are both glucogenic and ketogenic: isoleucine, phenylalanine, tyrosine, tryptophan, and threonine. All other amino acids are purely glucogenic.
Minor metabolic fates of amino acids are diverse, and the most important ones are discussed below.
Glycine is used as a precursor in the synthesis of heme and cholesterol. It also acts as an inhibitory neurotransmitter in the spinal cord.
Tyrosine is the source of the thyroid hormone thyroxine as well as the pigment melanin, made by melanocytes. It is also the precursor of the catecholamine neurotransmitters dopamine, norepinephrine, and epinephrine, produced by neurons in the central nervous system (CNS) and by chromaffin cells in the adrenal medulla.
Tryptophan is converted to serotonin (5-hydroxytryptamine or 5-HT) in CNS neurons and neuroendocrine cells of the intestinal tract. Serotonin affects gut motility, sleep, and mood. The pineal gland converts serotonin to melatonin. which helps regulate the sleep-wake cycle and allows the brain’s circadian rhythms to adjust to changes in day length.
Histidine is decarboxylated to form histamine. This reaction occurs in the CNS as well as in specialized intestinal cells called ECL cells. Basophils and mast cells store histamine inside cytosolic granules and release it during allergic reactions.
Lysine is the precursor of carnitine, a carrier molecule required for the transport of long chain fatty acids into the mitochondrial matrix.
Glutamate is the main excitatory neurotransmitter in the CNS. Some neurons decarboxylate glutamate to form GABA (gamma amino butyric acid), the nervous system’s main inhibitory neurotransmitter. Aspartate also serves as an excitatory neurotransmitter, mainly in spinal cord neurons.
Methionine is incorporated into a carrier molecule called SAM (S-adenosylmethionine), which plays a key role in the transport of methyl groups.
Genetic diseases involving amino acid catabolism (sometimes called inborn errors of metabolism) are relatively rare but can have devastating consequences. Phenylketonuria (PKU), caused by a defect in phenylalanine break down, occurs most often in Celtic populations, at a frequency of 1 in 25,000 newborns in the U.S. Infants with PKU must be placed on a special diet in the first six months of life, or severe mental retardation ensues.
Less common but more severe is maple syrup urine disease, which results from defective metabolism of the branched chain amino acids leucine, isoleucine, and valine. This disorder is seen almost exclusively in Amish populations, in an estimated 1 out of 380 births, as opposed to 1 in 185,000 births in the general population. Children with maple syrup urine disease seldom survive to adulthood, even with treatment.
An inability to metabolize glycine results in non-ketotic hyperglycinemia, or NKH, a disorder occurring most often in people of Finnish ancestry (1 in 55,000 births) and marked by seizures starting in infancy. Finally, a defect or absence of any enzyme of the urea cycle results in hyperammonemia, a life threatening condition characterized by loss of muscle tone, seizures, and if untreated, coma and death. Urea cycle defects occur in an estimated 1 out of 30,000 newborns.
Anabolism of amino acids is far less complicated in humans compared to most other organisms. Most plants, fungi, protozoa, and virtually all bacteria can synthesize all 20 amino acids from simple carbon and nitrogen containing precursors. Adult humans, on the other hand, must obtain 9 amino acids entirely from the diet. These are known as the essential amino acids, and a deficiency of even one of them can result in protein malnutrition, also called a negative nitrogen balance. The essential amino acids include phenylalanine, valine, tryptophan, threonine, isoleucine, methionine, histidine, leucine, and lysine. Arginine is an essential amino acid in children, but adults can obtain a sufficient amount from the urea cycle to avoid a negative nitrogen balance. A popular mnemonic for remembering the essential amino acids is PVT. TIM H(A)LL.
The non-essential amino acids are synthesized in the liver, mainly from the metabolic intermediates of glycolysis, the Krebs cycle, and urea cycle. Pyruvate and oxaloacetate are the precursors of alanine and aspartate, which in turn gives rise to asparagine. Another molecule produced in glycolysis, 3-PG, gives rise to serine, cysteine, and glycine. Glutamate is derived from the transamination of the Krebs cycle molecule alpha ketoglutarate; glutamate can be converted to glutamine and proline. As previously mentioned, arginine is produced in the urea cycle, where it acts as the immediate precursor of urea. Finally, tyrosine can be formed from the hydroxylation of phenylalanine. Technically, this makes tyrosine a non-essential amino acid; however, this holds true if and only if a person’s diet contains enough phenylalanine to divert some for tyrosine production.
