Pterin biosynthesis

O Donnell JM, McLean JR, Reynolds ER. 1989. Molecular and developmental genetics of the Punch locus, a pterin biosynthesis gene in Drosophila melano-gaster. Dev. Genet. 10 273-86... 

The first enzyme in the archaeal pterin pathway is a new type of GTP cyclohydrolase, MptA, coded by the MJ0775 gene in M. jannaschii Unlike the analogous GTP cyclohydrolase I enzymes found in bacteria that produce 7,8-dihydroneopterin 3 -triphosphate, the product of the M. jannaschii enzyme is H2neopterin-cP. This was consistent with the previous implication of this intermediate in archaeal pterin biosynthesis. MptA was also found to be unique among the known GTP cyclohydrolases in its requirement for Fe(II) for activity. The other GTP cyclohydrolases have all been characterized as Zn(II)-dependent enzymes. 

The biosynthesis processes of purines, pterins, and flavins are closely related. Both pterins and flavins are synthesized via the guanosine triphosphate (GTP) purine intermediate. 

There are a number of studies on the biosynthesis of various pteridines, i.e., xanthopterin (65), isoxanthopterin (67), erythropterin (73), leucopterin (68), and pterin (62) (509-511). The most important intermediate of the proposed biosynthetic pathway from guanosine triphosphate (GTP) (604) seems to be di-hydroneopterin triphosphate (H2-NTP) (605), however, because evidence has recently been accumulated indicating that pteridines such as biopterin (70), sepiapterin (81), and drosopterins (87) are synthesized from GTP (604) by way of H2-NTP (605) (Scheme 76) (5/2). 

The enzymes in the zebra fish pathway are presumably very similar to those of other vertebrates. However a completely different type of GTP cyclohydrolase has been identified in the hyperthermophilic euryarchaeon, Methanococcus jannashii <2002B15074>. This enzyme, in purified recombinant form, produced as a stable end product 2-amino-5-formylamino-6-ribofuranosylamino-4(3//)-pyrimidinone monophosphate, a compound that is an intermediate in the action of normal GTP cyclohydrolases. The biosynthesis of the incorporation of the pterin into methanopterin in Methanobacterium thermoautotrophicum has been proposed to occur via substitution of 7,8-dihydro-6-hydroxymethylpterin diphosphate 227 (Scheme 44) <1998BBA257>. 

The aromatic amino add hydroxylases (AAHs) are a family of pterin-dependent enzymes comprising phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH), and tryptophan hydroxylase (TPH, with two gene products TPH1 and TPH2). The AAHs perform the hydroxylation of aromatic amino adds and play an important role in mammalian metabolism and in the biosynthesis of... 

The hereditary absence of phenylalanine hydroxylase, which is found principally in the liver, is the cause of the biochemical defect phenylketonuria (Chapter 25, Section B).430 4308 Especially important in the metabolism of the brain are tyrosine hydroxylase, which converts tyrosine to 3,4-dihydroxyphenylalanine, the rate-limiting step in biosynthesis of the catecholamines (Chapter 25), and tryptophan hydroxylase, which catalyzes formation of 5-hydroxytryptophan, the first step in synthesis of the neurotransmitter 5-hydroxytryptamine (Chapter 25). All three of the pterin-dependent hydroxylases are under complex regulatory control.431 432 For example, tyrosine hydroxylase is acted on by at least four kinases with phosphorylation occurring at several sites.431 433 4338 The kinases are responsive to nerve growth factor and epidermal growth factor,434 cAMP,435 Ca2+ + calmodulin, and Ca2+ + phospholipid (protein kinase C).436 The hydroxylase is inhibited by its endproducts, the catecholamines,435 and its activity is also affected by the availability of tetrahydrobiopterin.436... 

Figure 25-19 The biosynthesis of folic acid and other pterins.

Keywords Biopterin Catecholamine biosynthesis Dystonia Hyperphenylalaninemia NO biosynthesis Pterin Tetrahydrobiopterin... 

The fifth chapter, Tetrahydrobiopterin and Related Biologically Important Pterins by Shizuaki Murata, Hiroshi Ichinose and Fumi Urano, describes a modern aspect of pteridine chemistry and biochemistry. Pteridine derivatives play a very important role in the biosynthesis of amino acids, nucleic acids, neurotransmitters and nitrogenmonooxides, and metabolism of purine and aromatic amino acids. Some pteridines are used in chemotherapy and for the diagnosis of various diseases. From these points of view, this article will attract considerable attention from medicinal and pharmaceutical chemists, and also heterocyclic chemists and biochemists. 

Chemical systems of relevance to the molybdenum and tungsten enzymes include synthetic pterins, a-phosphorylated ketones (as precursor models), and a variety of molybdenum and tungsten oxido, sulfido, and 1,2-enedithiolate complexes. These compounds have been used to (1) confirm the identity of MPT derivatives (2) define steps in MPT biosynthesis (3) calibrate spectroscopic observations (4) give precise geometries and reactivities that can be used as input for theoretical studies and (5) provide options for mechanistic consideration. 

The final topic addressed in this chapter is the biosynthesis of the dithiolene cofactor ligand and its coordination to molybdenum and tungsten in the enzymes. Nature has clearly devised a synthetic process to overcome the twin difficulties of building a reactive dithiolene unit bearing a complicated and equally reactive pterin substituent. Molecular biology has been the tool to elucidate the steps in this complex process. Although the dithiolene formation step remains mainly a subject of conjecture, definitive information about the reagent molecule that will eventually be converted to a dithiolene is known. 

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

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