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The enzyme dTDP-glucose 4,6-dehydratase (EC 4.2.1.46) catalyzes the chemical reaction

dTDP-glucose ${\displaystyle \rightleftharpoons }$ dTDP-4-dehydro-6-deoxy-D-glucose + H₂O

Structure and mechanism of action

The first protein structures of a dTDP-glucose 4,6-dehydratase (RmlB) were completed by Jim Thoden in the Hazel Holden lab (University of Wisconsin–Madison) and Simon Allard in the Jim Naismith lab (University of St Andrews). Further structural, mutagenic, and enzymatic studies by both groups, along with important mechanistic work by the W. Wallace Cleland and Perry Frey groups have led to a good understanding of this enzyme. In brief summary, the enzyme is a dimeric protein with a Rossmann fold; it uses the tightly bound coenzyme NAD for transiently oxidizing the substrate, activating it for the dehydration step.

Nomenclature

This enzyme belongs to the family of lyases, specifically the hydro-lyases, which cleave carbon-oxygen bonds. The systematic name of this enzyme class is dTDP-glucose 4,6-hydro-lyase (dTDP-4-dehydro-6-deoxy-D-glucose-forming). Other names in common use include thymidine diphosphoglucose oxidoreductase, TDP-glucose oxidoreductase, RmlB, DESIV, and dTDP-glucose 4,6-hydro-lyase. This enzyme participates in 4 metabolic pathways: nucleotide sugars metabolism, streptomycin biosynthesis, polyketide sugar unit biosynthesis, and biosynthesis of vancomycin group antibiotics.

References

1. Allard, STM; Cleland WW; Holden, HM. (2004). "High resolution X-ray structure of dTDP-glucose 4,6-dehydratase from Streptomyces venezuelae". Journal of Biological Chemistry. 279 (3): 2211–20. doi:10.1074/jbc.M310134200. PMID 14570895.
2. Allard, STM; Giraud, M-F; Naismith, JH; et al. (2001). "The crystal structure of dTDP-d-glucose 4,6-dehydratase (RmlB) from Salmonella enterica serovar typhimurium, the second enzyme in the dTDP-l-rhamnose pathway". Journal of Molecular Biology. 307 (1): 283–295. doi:10.1006/jmbi.2000.4470. PMID 11243820.
3. Hegeman AD, Gross JW, Frey PA (February 2002). "Concerted and stepwise dehydration mechanisms observed in wild-type and mutated Escherichia coli dTDP-glucose 4,6-dehydratase". Biochemistry. 41 (8): 2797–804. CiteSeerX 10.1.1.557.8752. doi:10.1021/bi011748c. PMID 11851427.
4. Gerratana B, Cleland WW, Frey PA (August 2001). "Mechanistic roles of Thr134, Tyr160, and Lys 164 in the reaction catalyzed by dTDP-glucose 4,6-dehydratase". Biochemistry. 40 (31): 9187–95. doi:10.1021/bi0108249. PMID 11478886.
5. Allard, STM; Beis K; Giraud MF; Hegeman AD; Gross JW; Wilmouth RC; Whitfield C; Graninger M; Messner P; Allen AG; Maskell DJ; Naismith JH (January 2002). "Toward a structural understanding of the dehydratase mechanism". Structure. 10 (1): 81–92. doi:10.1016/S0969-2126(01)00694-3. PMID 11796113.
6. Beis K, Allard; STM, Hegeman AD; Murshudov G; Philp D; Naismith JH (October 2003). "The structure of NADH in the enzyme dTDP-d-glucose dehydratase (RmlB)". J. Am. Chem. Soc. 125 (39): 11872–8. doi:10.1021/ja035796r. PMID 14505409.

Further reading

• Gilbert JM, Matshushi M, Strominger JL (1965). "Thymidine diphosphate 4-acetamido-4,6-dideoxyhexoses. II Purification and properties of thymidine diphosphate d-glucose oxidoreductase". J. Biol. Chem. 240: 1305–8. doi:10.1016/S0021-9258(18)97575-7. PMID 14284740.
• Melo A, Elliott WH, Glaser L (1968). "The mechanism of 6-deoxyhexose synthesis. I. Intramolecular hydrogen transfer catalyzed by deoxythymidine diphosphate D-glucose oxidoreductase". J. Biol. Chem. 243 (7): 1467–74. doi:10.1016/S0021-9258(18)93566-0. PMID 4869560.
• Wang SF, Gabriel O (1969). "Biological mechanisms involved in the formation of deoxy sugars. V Isolation and crystallization of thymidine diphosphate-D-glucose oxidoreductase from Escherichia coli B". J. Biol. Chem. 244 (13): 3430–7. doi:10.1016/S0021-9258(18)83390-7. PMID 4307450.

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