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Pterin Function in Bacteria

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Pterin Function in Bacteria Pteridines 2017; 28(1): 23–36 Review Nathan Feirer and Clay Fuqua* Pterin function in bacteria DOI 10.1515/pterid-2016-0012 important roles in diverse biological activities ranging Received December 12, 2016; accepted March 1, 2017; previously from immune system modulation, cellular signaling, col- published online April 19, 2017 oration, and metabolism. Pteridine rings are also impor- tant biosynthetic building blocks, forming the backbone Abstract: Pterins are widely conserved biomolecules that of several fundamental molecules including folic acid. play essential roles in diverse organisms. First described Several excellent reviews [1, 2] exist on the essential roles as enzymatic cofactors in eukaryotic systems, bacte- of folate in cell maintenance, nucleic acid synthesis, and rial pterins were discovered in cyanobacteria soon after. single-carbon metabolism; therefore, this review will Several pterin structures unique to bacteria have been focus on the roles of nonfolate pterin species. Despite a described, with conjugation to glycosides and nucleotides great deal of research on pteridine structure, synthesis, commonly observed. Despite this significant structural and function, many open questions exist in the field of diversity, relatively few biological functions have been elu- pterin biology. This is especially true in bacteria because cidated. Molybdopterin, the best studied bacterial pterin, much of the early research into pterins was performed plays an essential role in the function of the Moco cofac- studying eukaryotic systems. tor. Moco is an essential component of molybdoenzymes such as sulfite oxidase, nitrate reductase, and dimethyl sulfoxide reductase, all of which play important roles in bacterial metabolism and global nutrient cycles. Outside Early pterin research of the molybdoenzymes, pterin cofactors play important roles in bacterial cyanide utilization and aromatic amino Pterins were first discovered in the late 19th century acid metabolism. Less is known about the roles of pterins during the examination of yellow and blue fluorescent in nonenzymatic processes. Cyanobacterial pterins have pigments isolated from butterfly wings [3]. These reports been implicated in phenotypes related to UV protection were soon followed by observations of xanthopterin and and phototaxis. Research describing the pterin-mediated leucopterin present in fluorescent granules located in control of cyclic nucleotide metabolism, and their influ- gastrointestinal endocrine cells [4, 5]. The first example of ence on virulence and attachment, points to a possible a biological requirement for pterins was provided when role for pterins in regulation of bacterial behavior. In this Crithidia fasciculata, a trypanosomatid parasite of mos- review, we describe the variety of pterin functions in bac- quitoes, was shown to require a “Crithidia factor” for teria, compare and contrast structural and mechanistic proper growth in laboratory culture [6]. Originally thought differences, and illuminate promising avenues of future to be a folic acid derivative, further work showed that the research. “Crithidia factor” was an assemblage of structurally dis- tinct pteridine molecules that were required along with Keywords: cofactor; metabolism; pteridines; redox; folate for proper growth [7]. This pteridine requirement regulation. of Crithidia sp. for proper growth has been subsequently used to probe various bacterial families for the presence of pterin molecules [8]. Introduction Although it is not the focus of this review, a brief mention of the roles of pterins in eukaryotic organisms Pterins are ubiquitous compounds produced by organ- is warranted. After the initial discoveries listed above, a isms in all domains of life. These essential molecules play considerable amount of research has been conducted to determine the structure, biosynthesis, and function of *Corresponding author: Clay Fuqua, Department of Biology, Indiana various pterin molecules (thoroughly reviewed elsewhere University, Bloomington, IN 47405, USA, E-mail: [email protected]. http://orcid.org/0000-0001-7051-1760 [9–15]). Oxidized pterins such as neopterin have been Nathan Feirer: Department of Biology, Indiana University, shown to modulate the oxidative burst of reactive oxygen Bloomington, IN 47405, USA and nitrogen species in the human immune system [9, 16]. 24 Feirer and Fuqua: Bacterial pterins In addition, the immune system transcription factor NF-κβ function of the moa and moe class of biosynthetic genes is directly regulated by several pterin species in mammals [26]. Transcriptional control of molybdopterin biosyn- [17, 18]. Pterins also act as essential cofactors in several thetic and transport genes, although outside the scope of eukaryotic redox enzymes, a function that is shared with this review, can be an important aspect of their produc- many bacterial systems. tion [27–29]. In bacteria, pterins were first reported in the Cyano- Since the discovery of pterins in bacteria almost bacteria. Chromatographic fractionation of cell-free 60 years ago, intensive research into the function of these supernatants from Anabaena, Anacystis, and Nostoc led molecules has exposed the varied roles that they play in to isolation of several fluorescent molecules that exhib- bacterial ecosystems and environments. As with eukary- ited characteristics consistent with the pteridine ring otes, the role of pterins as redox cofactors was the primary structure [19]. Soon after, detailed biochemical characteri- focus of the majority of early bacterial pterin research. zation defined a biopterin glucoside from Anacystis nodu- More recent research has illuminated the role of pterin- lans [20]. In addition, several noncyanobacterial genera containing enzymes in aerobic and anaerobic meta- of photosynthetic bacteria such as Rhodospirillum and bolism, global nutrient cycles, detoxification of harmful Rhodopseudomonas were shown to produce pterin mole- compounds, pigment production, and utilization of non- cules that increased in abundance when these organisms canonical carbon and nitrogen sources. Pterins can also were grown in the light [21]. The discovery of xanthopterin play biological roles in addition to serving as enzymatic in Escherichia coli was among the first reports of pteri- cofactors, mediating processes including protection from dines from nonphotosynthetic organisms [22]. UV damage and intracellular signaling. Pterin synthesis, structure, Molybdoenzymes and the and general functions Moco cofactor The core pterin molecule is a nitrogen heterocycle com- Redox enzymes such as sulfite oxidase, nitrate reduc- posed of fused pyramidine and pyrazine rings with both tase, dimethyl sulfoxide (DMSO) reductase, and xanthine substituted keto and amino groups on the pyramidine dehydrogenase were first characterized in eukaryotes and ring (Figure 1). The synthesis of pterins in bacteria has mediate oxidation-reduction reactions involving a variety been well examined and a simplified bacterial biosyn- of different substrates [10, 26]. Redox enzymes, such as thetic pathway is presented in Figure 2. The biosynthetic those listed above, mediate oxygen transfer between sub- precursor to all pterin molecules is the purine nucleotide strate and water. All molybdoenzymes contain the Moco guanosine triphosphate (GTP). In bacteria, GTP cyclohy- cofactor in their active site, which facilitates electron drolase (EC 3.5.4.16, FolE in E. coli) converts GTP to dihy- transport during the redox reaction. Moco is composed of 6+ droneopterin triphosphate (H2NPt-P3) [23], which acts a molybdenum (Mo ) ion, which is conjugated within the as the biochemical precursor to folate, neopterin (NPt), enzyme active site via interactions through a molybdop- monapterin (MPt), and biopterin (BPt) [24]. These three terin molecule and amino acid functional groups of the types of pterins differ from each other by the side chain at cognate enzyme. Molybdopterin both modulates the oxi- position 6 of the pteridine ring (Figure 1). A recent report dation state of the Mo ion and enables electron transfer [25], characterizing a novel family of GTP cyclohydro- to other redox centers such as heme, iron-sulfur centers, lase enzymes, emphasizes the diversity of pterin meta- or flavins [10]. The requirement for a molybdopterin-con- bolism in divergent bacterial taxa. Further modification taining Moco cofactor is universal for all molybdoenzymes of NPt, MPt, and BPt is catalyzed by distinct enzymatic except nitrogenase, which contains only Mo. pathways. BPt species can be synthesized from H2NPt-P3 The core sulfur-containing, triple-ring structure of through a 6-pyruvoyltetrahydropterin (P-H4-Pt) interme- molybdopterin is conserved (Figure 1); however, in bac- diate. For NPt and MPt, an epimerization reaction, that teria molybdopterin can be found conjugated to guanine, may alternately occur at different points in the pathway, cystosine, adenine, or hypoxanthine dinucleotides [30– determines which species of pterin is produced [24]. 32]. As mentioned earlier, molybdopterin is synthesized Molybdopterin, the ubiquitous enzymatic cofactor that via a multistep enzymatic process [26] directly from a also contains a pteridine ring is synthesized directly from GTP precursor. This pathway is distinct from other known GTP via its own distinct pathway (Figure 2), requiring the pterin biosynthetic pathways in bacteria (Figure 2). Feirer and Fuqua: Bacterial pterins 25 Figure 1: Pterin chemical structures. Structures of the pteridine ring and select
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