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Pyridoxal 5 -Phosphate-Dependent Enzymes at the Crossroads of Host–Microbe Tryptophan Metabolism

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Pyridoxal 5 -Phosphate-Dependent Enzymes at the Crossroads of Host–Microbe Tryptophan Metabolism International Journal of Molecular Sciences Review 0 Pyridoxal 5 -Phosphate-Dependent Enzymes at the Crossroads of Host–Microbe Tryptophan Metabolism Barbara Cellini 1 , Teresa Zelante 1, Mirco Dindo 2, Marina M. Bellet 1, Giorgia Renga 1 , Luigina Romani 1 and Claudio Costantini 1,* 1 Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy; [email protected] (B.C.); [email protected] (T.Z.); [email protected] (M.M.B.); [email protected] (G.R.); [email protected] (L.R.) 2 Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0412, Japan; [email protected] * Correspondence: [email protected] Received: 15 July 2020; Accepted: 11 August 2020; Published: 13 August 2020 Abstract: The chemical processes taking place in humans intersects the myriad of metabolic pathways occurring in commensal microorganisms that colonize the body to generate a complex biochemical network that regulates multiple aspects of human life. The role of tryptophan (Trp) metabolism at the intersection between the host and microbes is increasingly being recognized, and multiple pathways of Trp utilization in either direction have been identified with the production of a wide range of bioactive products. It comes that a dysregulation of Trp metabolism in either the host or the microbes may unbalance the production of metabolites with potential pathological consequences. The ability to redirect the Trp flux to restore a homeostatic production of Trp metabolites may represent a valid therapeutic strategy for a variety of pathological conditions, but identifying metabolic checkpoints that could be exploited to manipulate the Trp metabolic network is still an unmet need. In this review, we put forward the hypothesis that pyridoxal 50-phosphate (PLP)-dependent enzymes, which regulate multiple pathways of Trp metabolism in both the host and in microbes, might represent critical nodes and that modulating the levels of vitamin B6, from which PLP is derived, might represent a metabolic checkpoint to re-orienteer Trp flux for therapeutic purposes. Keywords: tryptophan; microbiome; pyridoxal 50-phosphate 1. Introduction Tryptophan (Trp) is an aromatic amino acid characterized by the presence of a side chain indole, a bicyclic structure consisting of a benzene ring fused to a pyrrole ring [1]. The indole group is responsible for the peculiar structural and functional properties of Trp. Indeed, indole makes Trp a non-polar amino acid, which is important for stabilizing the structure of proteins, and is the scaffold of a series of Trp-derived metabolites with wide-ranging physiological activities [1] (Figure1). Trp metabolites can be generated not only by the host, but also by other organisms that interact with the host. For instance, the microbiota, i.e., the commensal microbes that inhabit the surfaces exposed to the external environment, such as the skin and the respiratory, gastrointestinal, and genitourinary tracts, can generate bioactive Trp metabolites [2]. Two characteristics make Trp an intriguing molecule in the relationship between the host and other organisms. First, Trp is an essential amino acid in mammals and needs to be acquired from the diet, whereas, in general, bacteria, fungi, and higher plants express enzymes for Trp biosynthesis. Second, the Trp metabolic pathways and the resulting bioactive molecules can either be shared or differ between mammals and other organisms [3]. All these characteristics create a network of inter-dependency and connectivity, centered around Trp and Int. J. Mol. Sci. 2020, 21, 5823; doi:10.3390/ijms21165823 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 5823 2 of 21 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 21 Trpmolded and molded by a plethora by a plethora of Trp-derived of Trp-derived metabolites, metabolit whiches, which is critical is critical for both for both the regulationthe regulation of host of hostphysiology physiology and and the the modulation modulation of of the the interaction interaction between between the the hosthost andand other organisms. organisms. Indeed, Indeed, aa dysregulation dysregulation of of Trp Trp metabolism metabolism has has been been associ associatedated with with the the occurrence occurrence of of diverse diverse pathological pathological conditionsconditions and and the the therapeutic therapeutic efficacy efficacy of ofbalancing balancing among among the the distinct distinct fates fates of Trp of Trp metabolism metabolism is increasinglyis increasingly being being recognized recognized [4]. [ 4This]. This therapeutic therapeutic effort effort would would benefit benefit from from a acomprehensive comprehensive assessmentassessment of of thethe complexitycomplexity of of Trp Trp metabolism metabolism in the in hostthe andhost microbes. and microbes. For instance, For instance, what orientates what orientatesthe flux of the Trp flux along of Trp the along different the metabolicdifferent metabolic pathways pathways in physiological in physiological conditions? conditions? Is there a commonIs there adenominator common denominator among all, among or at leastall, or some, at least of thesome, metabolic of the metabolic pathways? pathways? Is it possible Is it topossible identify to a identifycheckpoint a checkpoint that coordinates that coordinates the traffic of the Trp? traf Afic biochemical of Trp? A investigation biochemical ofinvestigation Trp metabolism of Trp may metabolismprovide an may interpretative provide an key interpretative to dissect this key complexity. to dissect this complexity. Figure 1. Schematic overview of the microbial and host tryptophan (Trp) and B6 vitamers metabolic Figurepathways. 1. Schematic The panel overview depicts of the the pathways microbial of and Trp host and B6tryptophan vitamers (Trp) metabolism and B6 invitamers the gut metabolic microbiota pathways.(pink, left The side) panel and depicts in the host,the pathways with particular of Trp an referenced B6 vitamers to the metabolism gut (yellow, in central) the gut and microbiota the liver (pink,(green, left right side) side) and metabolic in the host, pathways. with particular The green reference arrows to indicate the gut the (yellow, source orcentral) synthesis and ofthe Trp liver and (green,B6 vitamers, right side) the bluemetabolic arrows pathways. indicatethe The transport green arro amongws indicate the diff theerent source compartments, or synthesis and of Trp the blackand B6arrows vitamers, indicate the blue the metabolic arrows indicate reactions. the The transp panelort highlightsamong the the different distribution compartments, of pyridoxal and 50-phosphate the black arrows(PLP)-dependent indicate the enzymes metabolic in the reactions. microbes andThe thepanel host highlights governing the synthesisdistribution of key of Trppyridoxal metabolites, 5′- phosphateemphasizing (PLP)-dependent their dependence enzymes on B6 in vitamer the microbes availability. and the NAD: host Nicotinamidegoverning the adeninesynthesis dinucleotide. of key Trp metabolites,Details are describedemphasizing in the their main dependence text. on B6 vitamer availability. NAD: Nicotinamide adenine dinucleotide. Details are described in the main text. Vitamin B6 includes a group of chemically similar compounds, or vitamers, that are derivatives of 2-methyl-3-hydroxy-5-hydroxymethyl-pyridineVitamin B6 includes a group of chemically similar [5]. compounds, In the form or of vitamers, pyridoxal that 50-phosphate are derivatives (PLP) of(Figure 2-methyl-3-hydroxy-5-hydroxymethyl-pyridine2A), vitamin B6 works as a co-factor for more [5]. than In the 140 form enzymatic of pyridoxal reactions, 5′-phosphate corresponding (PLP) to (Figure4% of 2A), all classified vitamin B6 activities works as [6]. a Interestingly,co-factor for more critical than steps 140 in enzymatic the synthesis reactions, and metabolism corresponding of Trp to in ≈ ≈mammals4% of all classified and microbes activities are regulated[6]. Interestingly, by PLP-dependent critical steps enzymes. in the synthesis It is therefore and metabolism likely that vitaminof Trp inB6, mammals from which and the microbes active form are PLPregulated is derived, by PLP-dep might intersectendent theenzymes. Trp metabolism It is therefore to regulate likely its that flux vitaminalong the B6, di fromfferent which metabolic the active pathways, form PLP thus is deriv workinged, might as a metabolic intersect the checkpoint. Trp metabolism to regulate its fluxIn along this review,the different we provide metabolic an overviewpathways, of thus the working metabolic as dependence a metabolic betweencheckpoint. vitamin B6 and Trp in mammals and microbes, then discuss how the regulation of Trp flux may occur in function of vitamin B6 levels, and finally propose how the modulation of vitamin B6 levels may have potential therapeutic implications in pathological conditions. Int. J. Mol. Sci. 2020, 21, 5823 3 of 21 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 of 21 Figure 2. Schematic view of pyridoxal 50-phosphate (PLP) and catalytic mechanism of PLP enzymes. (AFigure) Chemical 2. Schematic structure view of PLP.of pyridoxal (B) Schematic 5′-phosphate depiction (PLP) of and the reactioncatalytic catalyzedmechanism by of PLP-dependent PLP enzymes. enzymes(A) Chemical with thestructure possible of outcomes.PLP. (B) Schematic depiction of the reaction catalyzed by PLP-dependent enzymes with the possible outcomes. 2. PLP-Dependent Enzymes in the Flux of Trp in Mammals
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