The Genetic Code Specifies 20 l-α-Amino Acids
Although more than 300 amino acids occur in nature, proteins are synthesized almost exclusively from the set of 20 l-α-amino acids encoded by nucleotide triplets called codons (see Table 37–1). While the three-letter genetic code could potentially accommodate more than 20 amino acids, the genetic code is redundant since several amino acids are specified by multiple codons. Scientists frequently represent the sequences of peptides and proteins using one- and three-letter abbreviations for each amino acid (Table 3–1). These amino acids can be characterized as being either hydrophilic or hydrophobic (Table 3–2), properties that affect their location in a protein’s mature folded conformation (see Chapter 5). Some proteins contain additional amino acids that arise by the post-translational modification of an amino acid already present in a peptide. Examples include the conversion of peptidyl proline and peptidyl lysine to 4-hydroxyproline and 5-hydroxylysine; the conversion of peptidyl glutamate to γ-carboxyglutamate; and the methylation, formylation, acetylation, prenylation, and phosphorylation of certain aminoacyl residues. These modifications significantly extend the biologic diversity of proteins by altering their solubility, stability, catalytic activity, and interaction with other proteins.
TABLE 3–2Hydrophilic & Hydrophobic Amino Acids ||Download (.pdf) TABLE 3–2 Hydrophilic & Hydrophobic Amino Acids
|Hydrophilic ||Hydrophobic |
Selenocysteine, the 21st Protein l-α-Amino Acid
Selenocysteine (Figure 3–1) is an l-α-amino acid found in proteins from every domain of life. Humans contain approximately two dozen selenoproteins that include certain peroxidases and reductases, selenoprotein P, which circulates in the plasma, and the iodothyronine deiodinases responsible for converting the prohormone thyroxine (T4) to the thyroid hormone 3,3'5-triiodothyronine (T3) (see Chapter 41). As its name implies, a selenium atom replaces the sulfur of its elemental analog, cysteine. Selenocysteine is not the product of a posttranslational modification, but is inserted directly into a growing polypeptide during translation. Selenocysteine thus is commonly termed the “21st amino acid.” However, unlike the other 20 protein amino acids, incorporation of selenocysteine is specified by a large and complex genetic element for the unusual tRNA called tRNASec which utilizes the UGA anticodon that normally signals STOP. However, the protein synthetic apparatus can identify a selenocysteine-specific UGA codon by the presence of an accompanying stem-loop structure, the selenocysteine insertion element, in the untranslated region of the mRNA (see Chapter 27).
Cysteine (left) & selenocysteine (right). pK3, for the selenyl proton of selenocysteine is 5.2. Since this is 3 pH units lower than that of cysteine, selenocysteine represents a better nucleophile at or below pH 7.4.
Stereochemistry of the Protein Amino Acids
With the sole exception of glycine, the α-carbon of every amino acid is chiral. Although some protein amino acids are dextrorotatory and some levorotatory, all share the absolute configuration of l-glyceraldehyde and thus are defined as l-α-amino acids. Even though almost all protein amino acids are (R), the failure to use (R) or (S) to express absolute stereochemistry is no mere historical aberration. l-Cysteine is (S) since the atomic mass of the sulfur atom on C-3 exceeds that of the amino group on C2. More significantly, in mammals the biochemical reactions of l-α-amino acids, their precursors and their catabolites are catalyzed by enzymes that act exclusively on l-isomers, irrespective of their absolute configuration.
Posttranslational Modifications Confer Additional Properties
While some prokaryotes incorporate pyrrolysine into proteins, and plants can incorporate azetidine-2-carboxylic acid, an analog of proline, a set of just 21 l-α-amino acids clearly suffices for the formation of most proteins. Posttranslational modifications can, however, generate novel R-groups that impart further properties. In collagen, for example, protein-bound proline and lysine residues are converted to 4-hydroxyproline and 5-hydroxylysine (Figure 3–2). The carboxylation of glutamyl residues of proteins of the coagulation cascade to γ-carboxyglutamyl residues (Figure 3–3) forms a chelating group for the calcium ion essential for blood coagulation. The amino acid side chains of histones are subject to numerous modifications, including acetylation and methylation of lysine and methylation and deamination of arginine (see Chapters 35 and 37). It also now is possible in the laboratory to genetically introduce many different unnatural amino acids into proteins, generating proteins via recombinant gene expression with new or enhanced properties and providing a new way to explore protein structure-function relationships.
4-Hydroxyproline & 5-hydroxylysine.
Extraterrestrial Amino Acids Have Been Detected in Meteorites
In February 2013, the explosion of an approximately 20,000 metric ton meteor in the skies above Chelyabinsk, Western Siberia, dramatically demonstrated the potential destructive power of those extraterrestrial bodies. However, not all the effects of meteors are necessarily undesirable. Some meteorites, the remnants of asteroids that have reached earth, contain traces of several α-amino acids. These include the protein amino acids Ala, Asp, Glu, Gly, Ile, Leu, Phe, Ser, Thr, Tyr, and Val, as well as biologically important nonprotein α-amino acids such as N-methylglycine (sarcosine) and β-alanine.
Extraterrestrial amino acids were first reported in 1969 following analysis of the famous Murchison meteorite from southeastern Australia. The presence of amino acids in other meteorites, including some pristine examples from Antarctica, has now been amply confirmed. Unlike terrestrial amino acids, these meteorites contain racemic mixtures of d- and l-isomers of 3- to 5-carbon amino acids, as well as many additional amino acids that lack terrestrial counterparts of biotic origin. In addition, nucleobases, activated phosphates and molecules related to sugars have also been detected in meteorites. These findings offer potential insights into the prebiotic chemistry of Earth, and impact the search for extraterrestrial life. Some speculate that, by delivering extraterrestrially generated organic molecules to the early earth, meteorites may have contributed to the origin of life on our planet.
l-α-Amino Acids Serve Additional Metabolic Roles
l-α-Amino acids fulfill vital metabolic roles in addition to serving as the “building blocks” of proteins. As discussed in later chapters, thyroid hormones are formed from tyrosine; glutamate serves as a neurotransmitter as well as the precursor of γ-aminobutyric acid (GABA); ornithine and citrulline are intermediates in urea biosynthesis; and homocysteine, homoserine, and glutamate-γ-semialdehyde participate in the intermediary metabolism of the protein amino acids (Table 3–3). The protein amino acids phenylalanine and tyrosine serve as precursors of epinephrine, norepinephrine, and DOPA (dihydroxyphenylalanine).
TABLE 3–3Examples of Nonprotein l-α-Amino Acids
Certain Plant l-α-Amino Acids Can Adversely Impact Human Health
The consumption of certain nonprotein amino acids present in plants can adversely impact human health. The seeds and seed products of three species of the legume Lathyrus have been implicated in the genesis of neurolathyrism, a profound neurological disorder characterized by progressive and irreversible spastic paralysis of the legs. Lathyrism occurs widely during famines, when Lathyrus seeds represent a major contribution to the diet. l-α-Amino acids that have been implicated in human neurologic disorders, notably neurolathyrism (Table 3–4) include l-homoarginine and β-N-oxalyl-l-α,β-diaminopropionic acid (β-ODAP). The seeds of the “sweet pea,” a Lathyrus legume that is widely consumed during famines, contain the osteolathyrogen γ-glutamyl-β-aminopropionitrile (BAPN), a glutamine derivative of β-aminopropionitrile (structure not shown). The seeds of certain Lathyrus species also contain α,γ-diaminobutyric acid, an analog of ornithine, that inhibits the hepatic urea cycle enzyme ornithine transcarbamoylase. The resulting disruption of the urea cycle leads to ammonia toxicity. Finally, l-β-methylaminoalanine, a neurotoxic amino acid present in Cycad seeds, has been implicated as a risk factor for neurodegenerative diseases including amyotrophic lateral sclerosis-Parkinson dementia complex in natives of Guam who consume either fruit bats that feed on cycad fruit, or flour made from cycad seeds.
d-Amino acids that occur naturally include free d-serine and d-aspartate in brain tissue, d-alanine and d-glutamate in the cell walls of gram-positive bacteria, and d-amino acids in certain peptides and antibiotics produced by bacteria, fungi, reptiles, and other nonmammalian species. Bacillus subtilis excretes d-methionine, d-tyrosine, d-leucine, and d-tryptophan to trigger biofilm disassembly, and Vibrio cholerae incorporates d-leucine and d-methionine into the peptide component of their peptidoglycan layer.