International Journal of Molecular Sciences Review The Uniqueness of Tryptophan in Biology: Properties, Metabolism, Interactions and Localization in Proteins Sailen Barik 3780 Pelham Drive, Mobile, AL 36619, USA; [email protected] Received: 2 November 2020; Accepted: 17 November 2020; Published: 20 November 2020 Abstract: Tryptophan (Trp) holds a unique place in biology for a multitude of reasons. It is the largest of all twenty amino acids in the translational toolbox. Its side chain is indole, which is aromatic with a binuclear ring structure, whereas those of Phe, Tyr, and His are single-ring aromatics. In part due to these elaborate structural features, the biosynthetic pathway of Trp is the most complex and the most energy-consuming among all amino acids. Essential in the animal diet, Trp is also the least abundant amino acid in the cell, and one of the rarest in the proteome. In most eukaryotes, Trp is the only amino acid besides Met, which is coded for by a single codon, namely UGG. Due to the large and hydrophobic π-electron surface area, its aromatic side chain interacts with multiple other side chains in the protein, befitting its strategic locations in the protein structure. Finally, several Trp derivatives, namely tryptophylquinone, oxitriptan, serotonin, melatonin, and tryptophol, have specialized functions. Overall, Trp is a scarce and precious amino acid in the cell, such that nature uses it parsimoniously, for multiple but selective functions. Here, the various aspects of the uniqueness of Trp are presented in molecular terms. Keywords: tryptophan; indole; virus; immunity; serotonin; kynurenine; codon 1. Introduction Tryptophan (Trp, W) is one of three aromatic amino acids that minimally contain a six-membered benzene ring in their side chains, the other two being phenylalanine (Phe, F) and tyrosine (Tyr, Y). Whereas Tyr is simply a p-hydroxy derivative of Phe, the side chain of Trp is indole, which is more complex, as it is a six-membered benzene ring fused to a five-membered pyrrole ring with an integrated NH group. Trp can also be viewed as a derivative of alanine (A), having an indole substituent on the β carbon (Table1). The indole ring of Trp absorbs strongly in the near-ultraviolet wavelength of the spectrum, with an absorption maximum at 280 nm, which forms the basis of measuring A280 as a characteristic assay for proteins, distinguishable from nucleic acids that have an absorption maxima at 260 nm. As presented later, the complex and nitrogenous aromatic side chain of Trp necessitates a large number of biosynthetic reactions, making Trp the most energetically expensive amino acid to synthesize. Discovered by Sir F.G. Hopkins in 1901 in milk casein hydrolysate, Trp was found to be an essential amino acid in experiments with mouse diet. Over the years, interest in Trp and its nutritional role in the mammalian diet has received enormous attention, much of which can be found in recent reviews [1–6]. Here, I have taken a complimentary approach, critically analyzing the major roles of Trp in cellular functions and in intermediary metabolism, such as translation, protein structure, adduct formation, the generation of important regulators, and most recently, RNA virus regulation. Int. J. Mol. Sci. 2020, 21, 8776; doi:10.3390/ijms21228776 www.mdpi.com/journal/ijms Review The Uniqueness of Tryptophan in Biology: Properties, Metabolism, Interactions and Localization in Proteins Sailen Barik 3780 Pelham Drive, Mobile, AL 36619, USA; [email protected] Received: 2 November 2020; Accepted: 17 November 2020; Published: 20 November 2020 Abstract: Tryptophan (Trp) holds a unique place in biology for a multitude of reasons. It is the largest of all twenty amino acids in the translational toolbox. Its side chain is indole, which is aromatic with a binuclear ring structure, whereas those of Phe, Tyr, and His are single-ring aromatics. In part due to these elaborate structural features, the biosynthetic pathway of Trp is the most complex and the most energy-consuming among all amino acids. Essential in the animal diet, Trp is also the least abundant amino acid in the cell, and one of the rarest in the proteome. In most eukaryotes, Trp is the only amino acid besides Met, which is coded for by a single codon, namely UGG. Due to the large and hydrophobic π-electron surface area, its aromatic side chain interacts with multiple other side chains in the protein, befitting its strategic locations in the protein structure. Finally, several Trp derivatives, namely tryptophylquinone, oxitriptan, serotonin, melatonin, and tryptophol, have specialized functions. Overall, Trp is a scarce and precious amino acid in the cell, such that nature uses it parsimoniously, for multiple but selective functions. Here, the various aspects of the uniqueness of Trp are presented in molecular terms. Keywords: tryptophan; indole; virus; immunity; serotonin; kynurenine; codon 1. Introduction Tryptophan (Trp, W) is one of three aromatic amino acids that minimally contain a six- membered benzene ring in their side chains, the other two being phenylalanine (Phe, F) and tyrosine (Tyr, Y). Whereas Tyr is simply a p-hydroxy derivative of Phe, the side chain of Trp is indole, which is more complex, as it is a six-membered benzene ring fused to a five-membered pyrrole ring with an integrated NH group. Trp can also be viewed as a derivative of alanine (A), having an indole substituent on the β carbon (Table 1). The indole ring of Trp absorbs strongly in the near-ultraviolet wavelength of the spectrum, with an absorption maximum at 280 nm, which forms the basis of Int.measuring J. Mol. Sci. 2020 A280, 21, as 8776 a characteristic assay for proteins, distinguishable from nucleic acids that have2 an of 22 absorption maxima at 260 nm. TableTable 1. 1.Codons Codons that that di differffer from from thethe TrpTrp codoncodon in the third (wobble) (wobble) base. base. StructureStructure of of CodonCodon Amino Acid Acid DistinguishingDistinguishing Property Property Side ChainChain (-R) (-R) Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 23 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 23 UGGUGG TrpTrp Aromatic,Aromatic, hydrophobichydrophobic Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 23 UCG Ser Hydroxyl, hydrophilic Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 23 UCG Ser Hydroxyl, hydrophilic GGG Gly None Smallest, flexible, no side chain UGC,GGGUCG UGU CysGlySer None Thiol,Smallest,Hydroxyl, hydrophilic flexible, hydrophilic (Serno side homolog) chain UGC,UCG UGU Cys SerSer Thiol,Hydroxyl,Hydroxyl, hydrophilic hydrophilichydrophilic (Ser homolog) UGC, UGU UGU CysCys Thiol,Thiol, hydrophilic (Ser (Ser homolog) homolog) Int.UGC, J. Mol.UUG UGUSci. 2020 , 21, x;Cys Leudoi: FOR PEER REVIEW Thiol, hydrophilicLarge,www.mdpi.com/journal/ijms hydrophobic (Ser homolog) UUG Leu Large,Large, hydrophobic UUG Leu Large, hydrophobic UUG Leu Large, hydrophobic AGG, CGGCGG ArgArg Basic,Basic, charged, hydrophilic hydrophilic AGG, CGG Arg Basic, charged, hydrophilic AGG, CGG Arg Basic, charged, hydrophilic 2. 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