Molybdenum cofactor biosynthesis

The molybdenum cofactor (Moco) is the essential component of a group of redox enzymes [20-22], which are diverse not only in terms of their phylogenetic distri- 

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Stallmeyer, B., Schwarz, G., Schulze, J., Nerlich, A., Reiss, J., Kirsch, j., and Mendel, R. R. The neurotransmitter receptor-anchoring protein gephyrin reconstitutes molybdenum cofactor biosynthesis in bacteria, plants, and mammalian cells, Proc Natl Acad Sci USA 1999, 96, 1333-1338. 

The condensation step is catalyzed by the glycosyltransferase SpcF. Further enzyme-catalyzed oxidation is probably needed for the introduction of the hemiketal linkage between cyclitol and sugar units. The SpcY enzyme, which has a similar counterpart, HygY, among the /lyg-cluster encoded proteins (see Section 2.2.4.3.1), is a candidate enzyme for this reaction. SpcY is a member of the radical SAM superfamily of proteins and relatives of SpcY have been found before all in connection with molybdenum-cofactor biosynthesis but to our knowledge no details of the mechanism involved is known for those. 

Schwarz G. Molybdenum cofactor biosynthesis and deficiency. Cell Mol. Life Sci. 2005 62 2792-2810. 

Moco is essential for the activity of sulfite oxidase, XDH, and AO, the three molybdoenzymes present in humans. Human Moco deficiency leads to the pleiotropic loss of all three of these molybdoenzymes and usually progresses to death at an early age. In humans, a combined deficiency of sulfite oxidase and XDH was first described by Duran et al To date, more than 100 cases of Moco deficiency or isolated sulfite oxidase deficiency are known worldwide. Isolated sulfite oxidase deficiency is a related disease in which molybdenum cofactor biosynthesis is normal, but sulfite oxidase activity is altered. The clinical symptoms of Moco deficiency are indistinguishable from those of isolated sulfite oxidase deficiency with a notable exception that xanthinuria is absent in the latter. In both cases, affected neonates show feeding difficulties, neurological abnormalities such as attenuated brain growth, untreatable seizures, dislocated ocular lenses in most cases, and death in early childhood. Although milder symptoms are occasionally observed, none of the treatments tested... 

WuEBBENS MM, Liu MT, Rajagopalan K and ScHiNDELiN H (2000) Insists into molybdenum cofactor deficiency provided by the crystal structure of the molybdenum cofactor biosynthesis protein MoaG. Structure Fold Des 8 709-718. 

The deficiencies of cystathionine )5-synthase (CBS), sulfite oxidase, and methylenetetrahydrofolate reductase (MTHFR) may all result in central nervous system dysfunction, in particular mental retardation [1-3]. Defects of CBS and sulfite oxidase both cause dislocated lenses of the eyes, but the phenotypes are different otherwise. The manifestations of CBS deficiency, the most common of these disorders, and MTHFR deficiency range from severely affected to asymptomatic patients both may cause vascular occlusion. Deficiency of sulfite oxidase is clinically uniform, but genetically heterogeneous, and functional deficiency of the enzyme can result from several inherited defects of molybdenum cofactor biosynthesis [2, 4]. Hereditary folate malabsorption and defects of cobalamin transport (transcobala-min II deficiency) or cobalamin cofactor biosynthesis (cblC-G diseases) may cause megaloblastic anemia, in addition to CNS dysfunction [3, 5, 6]. 

As well as donating electrons to the MoFe protein, the Fe protein has at least two and possibly three other functions (see Section IV,C) It is involved in the biosynthesis of the iron molybdenum cofactor, FeMoco it is required for insertion of the FeMoco into the MoFe protein polypeptides and it has been implicated in the regulation of the biosynthesis of the alternative nitrogenases. 

Figure 3.10 Biosynthesis of eukaryotic molybdenum cofactor occurs in four steps. (Adapted from Mendel and Bittner, 2006. Copyright 2006, with permission from Elsevier.)...

Rajagopalan, K. V. Biosynthesis and processing of the molybdenum cofactors, Biochem Soc Trans 1997, 25, 757-761. 

Matthies, a., Rajagopalan, K. V., Mendel, R. R., and Leimkuhler, S. Evidence for the physiological role of a rhodanese-like protein for the biosynthesis of the molybdenum cofactor in humans, Proc Natl Acad Sci USA 2004, 303, 5946-5951. 

K), Fe-S cluster assembly (nIfM) and the biosynthesis of the iron molybdenum cofactor, FeMo-co (nifN, B, E, Q, V, H)(5a). It is the last two functions, involving the placement of unusual transition metal sulfide clusters into the nitrogenase proteins, that cause nitrogenase and its components to be appropriately included in this symposium. 

Aldehyde oxidase purified from maize coleoptiles is a multicomponent enzyme that contains a molybdenum cofactor, nonheme iron, and flavin adenine dinucleotide (FAD) as prosthetic groups.111 When substrate specificity of the aldehyde oxidase was tested, good activity was detected with IAAld, indole-3-aldehyde, and benzaldehyde among others. The addition of NADP and NADPH did not change the activity. In contrast, in maize endosperm, tryptophan-dependent IAA biosynthesis was dependent on an NADP/NADPH redox system, which may mean that the two tissues of maize are utilizing different pathways or different redox systems for IAA biosynthesis.112... 

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