Structures and reaction mechanisms of GTP cyclohydrolases

Abstract

GTP cyclohydrolases generate the first committed intermediates for the biosynthesis of certain vitamins/cofactors (folic acid, riboflavin, deazaflavin, and tetrahydrobiopterin), deazapurine antibiotics, some t-RNA bases (queuosine, archaeosine), and the phytotoxin, toxoflavin. They depend on divalent cations for hydrolytic opening of the imidazole ring of the substrate, guanosine triphosphate (GTP). Surprisingly, the ring opening reaction is not the rate-limiting step for GTP cyclohydrolases I and II whose mechanism have been studied in some detail. GTP cyclohydrolase I, Ib, and II are potential targets for novel anti-infectives. Genetic factors modulating the activity of human GTP cyclohydrolase are highly pleiotropic, since the signal transponders whose biosyntheses require their participation (nitric oxide, catecholamines) impact a very wide range of physiological phenomena. Recent studies suggest that human GTP cyclohydrolase may become an oncology target. V C 2013 IUBMB Life, 65(4):310-322, 2013Keywords: GTP cyclohydrolase; biosynthesis; pteridines; folate; riboflavin; reaction mechanismThe chromophores of several universal or wide-spread coenzymes including the flavin cofactors, FMN and FAD, the deazaflavins derived from 7,8-didemethyl-8-hydroxy-5-deazariboflavin, the one-carbon transponders tetrahydrofolate (1) and tetrahydromethanopterin (4), and the redox cofactor tetrahydrobiopterin (2) are all derived from GTP (Scheme 1). The cofactor chromophores retain the pyrimidine ring carbon atoms, the nitrogen atoms 1, 3, and 9, and the position 4 carbonyl oxygen of the GTP precursor. Some coenzymes also retain N-7, the position 2 amino group and three carbon atoms of the ribosyl side chain, respectively. The chromophores are the business ends of the cofactors serving as redox transponders (flavins, deazaflavins, and tetrahydrobiopterin), onecarbon transponders (folates and methaonopterin), or photoreptors (flavins, deazaflavins, and folate derivatives).Work started in the 1950s had established that the chromophores of flavins and of folate are derived from a guanine nucleotide (for review see refs. 1,2). The biosynthesis of the GTP-derived cofactors in Scheme 2 starts with the opening of the imidazole ring of the nucleotide catalyzed by metal-dependent GTP cyclohydrolases (specifically, GTP cyclohydrolases I, Ia, II, III, and MptA) affording four different biosynthesis intermediates (dihydroneopterin 3 0 -triphosphate (10), dihydroneopterin 2 0 ,3 0 -cyclophosphate (11), 2,5-diamino-6-ribosylamino-4(3H)-pyrimidinone 5 0 -phosphate (12), and 2-amino-5-formylamino-6-ribosylamino-4(3H)-pyrimidinone 5 0 -phosphate (13) (Scheme 2).The ''classical'' GTP cyclohydrolases, that is GTP cyclohydrolases I catalyzing the first committed step in the biosynthetic pathways of tetrahydrofolate and tetrahydrobiopterin, and GTP cyclohydrolase II catalyzing the first committed step in the biosynthesis of riboflavin were discovered in the 1970s. Both enzymes have been studied in considerable detail over the following decad...

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“…6A) (21). The first half of the reaction comprises two sequential hydrolysis reactions that result in purine ring opening and release of formic acid to give 2,5-diamino-6-ribosylamino-4(3H)-pyrimidinone 5′-triphosphate (compound II) (Fig.…”

The Enzymology of Organic Transformations: A Survey of Name Reactions in Biological Systems

“…The same reaction is also involved in the biosynthesis of tetrahydrobiopterin ( 227 ), a cofactor required for phenylalanine hydroxylase and nitric oxide synthase, and 7-deazapurine ( 228 ), which is a key component of hypermodified tRNA nucleosides (such as queuosine, 229 ) and nucleoside antibiotics (such as toyocamycin, 230 , Figure 61b). [230] …”

Biochemical and functional characterization of Plasmodium falciparum GTP cyclohydrolase I

“…GCH1 is a well-conserved protein found in bacteria, protozoa, plants and animals including human [26,27]. The enzyme converts GTP into 7,8 dihydroneopterin triphosphate, the precursor of the pterin moiety in folate derivatives (Figure 1) [26].…”

“…The enzyme converts GTP into 7,8 dihydroneopterin triphosphate, the precursor of the pterin moiety in folate derivatives (Figure 1) [26]. The enzyme forms a homodecameric barrel-like structure with ten zinc-containing active sites with each of them formed between three subunits [26].…”

“…The enzyme converts GTP into 7,8 dihydroneopterin triphosphate, the precursor of the pterin moiety in folate derivatives (Figure 1) [26]. The enzyme forms a homodecameric barrel-like structure with ten zinc-containing active sites with each of them formed between three subunits [26]. The enzyme catalyzes the breakages of the guanine and ribose rings in GTP and rearranges them to form 7,8-dihydroneopterin triphosphate (Figure 1) [26,28].…”