DTDP-glucose 4,6-dehydratase explained

dTDP-glucose 4,6-dehydratase
Altnames:	RmlB
Ec Number:	4.2.1.46
Cas Number:	37259-54-4
Go Code:	0008460

The enzyme dTDP-glucose 4,6-dehydratase catalyzes the chemical reaction

\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).^{[1] [2]} 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.^{[3] [4]} 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.^{[5] [6]}

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.

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 . 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 . 1467 - 74 . 4869560 . 7 .
• 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 . 3430 - 7 . 4307450 . 13 .

Notes and References

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