Guanosine triphosphate cyclohydrolase

A Fig. 6.1.7a- HPLC of pterins using a column-switching system a standard mixture b control urine c urine guanosine triphosphate cyclohydrolase I (GTPCH) deficiency d urine 6-pyru-voyl-tetrahydropterin synthase (PTPS) deficiency e urine pterin-4a-carbinolamine dehydratase (PCD) deficiency f urine dihydropteridine reductase (DHPR) deficiency g urine phenylketonuria 4-8 h after tetrahydrobiopterin (BH4) administration h-k see next page... 

Naylor EW, Ennis D, Davidson AG, Wong LT, Applegarth DA, Niederwieser A, Guanosine triphosphate cyclohydrolase I deficiency early diagnosis by routine urine pteridine screening. Pediatrics 1987 79 374-8. 

Tabraue, C., Penate, R.D., Gallardo, G., Hernandez, I., Quintana, J., Blanco, F.L., Reyes, J.G., Fanjul, L.F., and Ruiz De Galarreta, C.M. (1997). Induction of guanosine triphosphate-cyclohydrolase by follicle-stimulating hormone enhances interleukin-1 P-stimulated nitric oxide synthase activity in granulosa cells. Endocrinology 738 162-168. 

Krungkrai, J., Yuthavong, Y., and Webster, H. K. (1985). Guanosine triphosphate cyclohydrolase in Plasmodium falciparum and other Plasmodium species. Mol. Biochem. Parasitol. 17, 265-276. 

Guanosine triphosphate cyclohydrolase I 2 pyrophosphorylase, phosphatase 3 diliydro-neopterin aldolase 4 hydroxymethyldihydropterin pyrophosphokinase 5 dihydropteroate synthase 6 dihydrofolate synthetase 7 dihydrofolate reductase 8 xanthine oxidase... 

OPRMl, Mu opioid receptor COMT, catechol-O-methly transferase CYP2D6,cytochrome 2D6 MCIR, melanocortin-1-receptor GCHl, guanosine triphosphate cyclohydrolase-1 ABCBl, ATP-binding cassette, sub-family B, member 1. 

Neopterin. Neopterin is a low-molecular-weight substance derived from guanosine triphosphate (GTP) via the enzyme GTP-cyclohydrolase 1. Numerous investigators have demonstrated that neopterin, a product of human macrophages stimulated by y interferon and other cytokines, is a useful in vivo marker of the activation of cellular immunity (U4, Wl). Increased values of neopterin in body fluids have been reported in patients with malignancy, infections, and several inflammatory states. 

The precursors for riboflavin biosynthesis in plants and microorganisms are guanosine triphosphate and ribulose 5-phosphate. As shown in Figure 7.3, the first step is hydrolytic opening of the imidazole ring of GTP, with release of carbon-8 as formate, and concomitant release of pyrophosphate. This is the same as the first reaction in the synthesis ofpterins (Section 10.2.4), but utilizes a different isoenzyme of GTP cyclohydrolase (Bacher et al., 2000, 2001). 

Guanosine triphosphate and ribulose-5-phosphate are recruited in a 1 2 stoichiometric ratio by GTP cyclohydrolase II and DHBP synthase, respectively, for riboflavin biosynthesis. Since at substrate saturation the activity of B. subtilis DHBP is twice the activity of B. suhtilis cyclohydrolase II (DSM, unpublished observations) and since both enzymatic activities are associated with the same bifunctional protein encoded by rihA, the balanced formation of the pyrimidinedione and the dihydroxybutanone intermediates is ensured. However, the ifg.s constant of DHBP synthase ( 1 mmol is about 100-fold higher than the ifg.s constant of GTP cyclohydrolase II imposing the risk of excessive synthesis of the pyrimidinone and pyrimidinedione intermediates in case of reduced intracellular concentrations of pentose phosphate pathway intermediates. This can be expected, for instance, in glucose-limited fed-batch fermentations, which are frequentiy used in industrial applications. The pyrimidinone and pyrimidinedione intermediates are highly reactive, oxidative compounds, which can do serious damage on the bacteria. 

Riboflavin biosynthesis [301] in prokaryotes starts from guanosine triphosphate and ribulose-5-phosphate in a 1-2M ratio, respectively (Figure 7.5). The hydrolytic opening of the imidazole ring of GTP (RibA cyclohydrolase II reaction) is followed by (i) deamination of the resulting pyrimidinone to afford... 

Scheme 12.118. The conversion of guanosine triphosphate (GTP) to 7,8-dihydroneopterin under the influence of GTP cyclohydrolase I (EC 3.5.4.16). EC numbers and some graphic materials provided in this scheme have been taken from appropriate links in a URL starting with http //www.chem.qmul.ac.uk/inbmb/enzyme/.

Mechanistic studies on the formation of the molybdopterin cofactor are still at an early stage. Conversion of guanosine, presumably as the triphosphate, to precursor Z occurs with retention of C-8 [84]. A possible mechanism for this third type of cyclohydrolase, which is consistent with the labeling experiment, is outlined in Fig. 20. (The other two types of cyclohydrolase are cyclohydrolase 1 for folate biosynthesis and cyclohydrolase II for riboflavin biosynthesis. In both cases, C8 is removed as formate.)... 

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