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Chirality of Amino Acids Modulates Mammalian Physiology and Pathology

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Chirality of Amino Acids Modulates Mammalian Physiology and Pathology REVIEW Distinctive Roles of d-Amino Acids in the Homochiral World: Chirality of Amino Acids Modulates Mammalian Physiology and Pathology Jumpei Sasabe1 and Masataka Suzuki1,2 1Department of Pharmacology, Keio University School of Medicine, Tokyo, Japan 2Research Fellow of the Japan Society for the Promotion of Science (JSPS), Tokyo, Japan (Received for publication on January 21, 2018) (Revised for publication on April 2, 2018) (Accepted for publication on April 5, 2018) (Published online in advance on May 22, 2018) Living organisms enantioselectively employ l-amino acids as the molecular architecture of protein syn- thesized in the ribosome. Although l-amino acids are dominantly utilized in most biological processes, accumulating evidence points to the distinctive roles of d-amino acids in non-ribosomal physiology. Among the three domains of life, bacteria have the greatest capacity to produce a wide variety of d- amino acids. In contrast, archaea and eukaryotes are thought generally to synthesize only two kinds of d-amino acids: d-serine and d-aspartate. In mammals, d-serine is critical for neurotransmission as an endogenous coagonist of N-methyl d-aspartate receptors. Additionally, d-aspartate is associated with neurogenesis and endocrine systems. Furthermore, recognition of d-amino acids originating in bacteria is linked to systemic and mucosal innate immunity. Among the roles played by d-amino acids in human pathology, the dysfunction of neurotransmission mediated by d-serine is implicated in psychiatric and neurological disorders. Non-enzymatic conversion of l-aspartate or l-serine residues to their d-config- urations is involved in age-associated protein degeneration. Moreover, the measurement of plasma or urinary d-/l-serine or d-/l-aspartate levels may have diagnostic or prognostic value in the treatment of kidney diseases. This review aims to summarize current understanding of d-amino-acid-associated biology with a major focus on mammalian physiology and pathology. (DOI: 10.2302/kjm.2018-0001- IR) ; Keio J Med ** (*) : **–**, mm yy) Keywords: chirality, d-amino acid, cell wall, neurobiology, innate immunity Introduction tartaric acid more than 150 years ago. The right-handed (dextro-: d-enantiomer) and left-handed molecule (levo-: Chirality is a property of objects that are non-super- l-enantiomer) have identical molecular mass with equiv- imposable on their mirror image. The two forms of a alent chemical and physical energy, but the manner in chiral object are called enantiomers. Many living organ- which they interact with other molecules is different, just isms possess macroscopic chirality, e.g. the shells of most as a right hand interacts differently with left- and right- snails form right-handed spirals. Human morphology hand gloves (Fig. 1). Mysteriously, living organisms uti- also has chirality: the heart is located on the left side and lize only a single enantiomer in each biological process. the liver is arranged on the right. There are two major facts relating to the single chirality of The concept of molecular chirality has fascinated scien- biological molecules: most sugars are d-sugars and most tists since Pasteur first separated enantiomeric crystals of amino acids are l-amino acids. Without some type of chi- Reprint requests to: Jumpei Sasabe, MD, PhD, Department of Pharmacology, School of Medicine, Keio University, 35 Shinanomachi, Shinju- ku-ku, Tokyo 160-8582, Japan, E-mail: [email protected] Copyright © 2018 by The Keio Journal of Medicine 1 2 Sasabe J and Suzuki M: Roles of d-Amino Acids in Mammals ents to support bacterial growth,4–7 to regulate bacterial spore germination,8–10 and as components of bacterial cell walls11 and some bacterial peptide antibiotics12 (Fig. 2). The discovery by Snell in 1945 that d-Ala is a growth factor in the absence of vitamin B6 for Streptococcus fae- calis and Lactobacillus casei13,14 led to a series of stud- ies which ultimately revealed the essential requirement of d-Ala as a component of peptidoglycan found in the cell walls of virtually all bacteria. d-Ala and d-Glu are by far the most common d-amino acids present in the bacterial Fig. 1 . d- and l-configurations of a chiral amino acid. R is the cell wall; however, the peptidoglycan of some bacteria side chain of the amino acid. includes other d-amino acids, such as d-Asp in Lacto- coccus15 and Enterococcus,16 and d-Ser in vancomycin- resistant Staphylococcus aureus.17–19 These d-amino ac- ral influence, a chemical reaction that makes a product ids are synthesized by amino acid racemases – enzymes with a chiral center will always yield equal amounts of d- that catalyze the stereochemical inversion of biological and l-enantiomers (called a racemic mixture), and, there- molecules. To date, more than 10 kinds of racemases fore, it is considered that sugars and amino acids were have been identified in bacteria.20 The resulting d-amino racemic in primordial Earth before the emergence of life. acids may be incorporated into the peptides via a non- Although the processes that changed the initially racemic ribosomal peptide (NRP) synthetic pathway that gener- world and how such bias was sustained and propagated ates peptides independent of the chiral selection of amino into the current homochiral world remain controversial acids by transfer RNA. The presence of d-amino acids (nicely reviewed by Blackmond),1 biological evolution re- in peptidoglycan contributes to cross-linking repeated di- sulted in the exclusive use of l-amino acids in ribosomal saccharide units that form a mesh-like architecture and protein synthesis and d-sugar (d-ribose) in nucleotides. provides resistance to most known proteases.21 Recently, The resulting homochirality enables consistent protein it has become clear that various free d-amino acids, in- foldings and forms the immutably right-handed helix of cluding d-Met, d-Leu, d-Tyr, and d-Phe, are also synthe- DNA. Because the aminoacylation of transfer RNA is sized and released by bacteria from diverse phyla at up to the first step of ribosomal protein synthesis, this reac- millimolar concentrations.22 Furthermore, these released tion could have provided the chiral selectivity of amino d-amino acids function to regulate cell wall chemistry acids in protein. Interestingly, there is a clear preference and architecture22 as well as to promote biofilm develop- of l-amino acids for nonprotein RNA-directed aminoac- ment in bacteria.23 ylation of RNA minihelices composed of d-ribose as the sugar backbone, and a mirror-image RNA system shows 2. d-Amino Acids in the Domain Archaea the opposite selectivity.2 Therefore, the l-amino acid ho- mochirality of proteins could be determined by the ho- In contrast to the relative abundance of d-amino ac- mochirality of RNA, which has a d-ribose configuration. ids in bacteria, much fewer studies have reported the RNA chirality may, in turn, have been influenced by pre- occurrence of d-amino acids in archaea. Archaea form biotic amino acids that were chiral catalysts for the syn- one of three domains of life and are a group of single- thesis of d-sugars.3 Although the mechanism underlying celled prokaryotic organisms predominantly with a cell the initial imbalance of d-/l-amino acids or d-/l-sugars wall. Among the distinct molecular characteristics that on the primordial Earth is not understood, d-amino acids differentiate archaea from bacteria, one is the composi- and l-sugars were selectively excluded from living sys- tion of the cell wall (Fig. 2). Whereas peptidoglycan is a tems after a long chain of events that might constitute an standard component of all bacterial cell walls, archaeal essential process for the development and maintenance cell walls lack peptidoglycan, with the exception of some of life. Consequently, it was initially believed that only a methanogens, such as Methanobacteriales and Metha- single enantiomer of each class of compounds occurred nopyrus.24 The cell walls of these exceptional groups of in nature, and l-sugars and d-amino acids were regarded archaea are composed of a peptidoglycan-like structure, as laboratory artifacts and categorized as “unnatural iso- called pseudopeptidoglycan, which has a similar physical mers”; however, this is not in fact the case. structure to that of bacterial peptidoglycan but includes cross-linking peptides made up of only l-amino acids.25 1. d-Amino Acids in the Domain Bacteria Therefore, archaea do not utilize d-amino acids as build- ing blocks for their cell walls. However, there are several Bacteria were among the first life forms to appear on reports of the occurrence of d-amino acids in archaea, Earth and have the largest genetic capacity to metabo- such as d-Asp in some hyperthermophilic archaea26,27 lize d-amino acids. d-Amino acids are utilized as nutri- and in Thermoplasma acidophilum,28 and d-Ser in Py- Keio J Med yy; ** (*): **–** 3 Fig. 2 . Cell walls of bacteria, archaea, and eukaryotes. d-Amino acids are integral components of bacterial cell walls but are not used in those of archaea or eukaryotes. Chloroplasts and mitochondria are essential eukaryotic organelles of endosymbiotic origin that arose from an alpha-proteobacterial or a cyanobacterial ancestor. Bacterial genes to synthesize d-amino acids were subjugated by the host cells, and the peptidoglycan layers of those ancestors are not found in the organelles. robaculum islandicum,29 although their functions are 3.1. d-Amino acids in the animal kingdom of eukary- not well understood. A more recent report states that Py- otes rococcus horikoshii, a hyperthermophilic archeon, me- tabolizes several d-amino acids with a broad-spectrum A few kinds of d-amino acids, mainly d-Ala/d-Ser/d- racemase for their growth,30 suggesting that a group of Asp, have been detected in a variety of eukaryotes as free archaea fully utilizes d-amino acids as nutrients obtained amino acids or, rarely, as components of peptides and in the extreme environments in which they live.
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