Mechamsms for the ring conventon of GTP mto cofactor precursors by GTP cyclohydrolases and molybdopterin synthase are proposed and discussed III the context of the crystal structllre of the GTP cyclohydrolase I -2'-deoxy-GTT' complex The mechatusms suggest that common features of acid-base catalysis may underly the reactions catalysed m all three cases 0 1997 Elsevier Science Ltd. GTP-cyclohydrolases 1 and II (GTPCH-I and II) catalyse the first commited stages in the biosynthetic pathways leading respectively to folate and biopterin cofactors. and to flavin cofactors.' The involvement of this wide range of cofactors in metabolic transformations inchding the biosynthesis of nucleic acids, of essential amino acids and hormones. and in such fundamental processes as oxidation gives the GTP-cyclohydrolases special importance.' The occurence and genetics of these enzymes in many species has been widely studied but their mechanism of action has been little more than surmised from the overall chemical reactions that they catalyse. The availability of genes coding for these enzymes has made it possible to obtain sign&ant quantities of the wild type enzymes and mutant?. Recently. a crystal structure of GTPCH-I at 3A resolution has been described4 providing the first substantial basis for a molecular understanding of the mechanism of action. Structural information is also available for GTPCH-II from two sources, Bacillus subtrlis and Eschemhra coli;' the enzymes from the two sources appear to have little sequence homology. A third cofactor class, the MO cofactors (molybdopterin), also appears to be derived from GTP." GTPCH-I apparently catalyses a complex series of reactions in which the imidazole and ribose rings of GTP are opened, C-S is lost as formate. and the ribose fragment undergoes Amadori rearrangement and recyclisation to form dihydroneopterin triphosphate (figure la).' Nothing is known about the elementary steps of these reactions. GTPCH-II catalyses part of this process leading simply to loss of C-8 as formate and may follow only one part of the GTPCH-I pathway (figure lb).X Precursor Z has been proposed to be derived from GTP via a complex series ofreactions that could be related to the cyclohydrolases although none of the carbon atoms of GTP appears to be lost in the transformation (figure Ic).'
The fact that these three enzymes each lead to cofactors of great biosynthetic significance suggests that they may be early enzymes in evolutionary terms as has been implied by Golding in the case of B,?-mediated rearrangements.'" Further, since they supply cofactors it is possible that they are not highly evolved with respect to catalytic efficiency because a small quantity of cofactor would suffice the demands of many metabolic enzymes of higher efficiency. Two of these enzymes, GTPCH-I and precursor Z synthase, catalyse a complex series of events including ring openings and recyclisations. In each case, the purine ring is converted into a pteridine.