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Crystal structure of human gamma-butyrobetaine hydroxylase
Authors:Kaspars Tars  Janis Rumnieks  Andris Kazaks  Ainars Leonciks  Arturs Viksna  Edgars Liepinsh
Institution:a Biomedical Research and Study Centre, Ratsupites 1, LV1067, Riga, Latvia
b Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, LV1013, Riga, Latvia
c Latvian Institute of Organic Synthesis, Aizkraukles 21, LV1006, Riga, Latvia
Abstract:Gamma-butyrobetaine hydroxylase (GBBH) is a 2-ketoglutarate-dependent dioxygenase that catalyzes the biosynthesis of l-carnitine by hydroxylation of gamma-butyrobetaine (GBB). l-carnitine is required for the transport of long-chain fatty acids into mitochondria for generating metabolic energy. The only known synthetic inhibitor of GBBH is mildronate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate), which is a non-hydroxylatable analog of GBB.To aid in the discovery of novel GBBH inhibitors by rational drug design, we have solved the three-dimensional structure of recombinant human GBBH at 2.0 Å resolution. The GBBH monomer consists of a catalytic double-stranded β-helix (DBSH) domain, which is found in all 2KG oxygenases, and a smaller N-terminal domain. Extensive interactions between two monomers confirm earlier observations that GBBH is dimeric in its biological state. Although many 2KG oxygenases are multimeric, the dimerization interface of GBBH is very different from that of related enzymes.The N-terminal domain of GBBH has a similar fold to the DUF971 superfamily, which consists of several short bacterial proteins with unknown function. The N-terminal domain has a bound Zn ion, which is coordinated by three cysteines and one histidine. Although several other 2KG oxygenases with known structures have more than one domain, none of them resemble the N-terminal domain of GBBH. The N-terminal domain may facilitate dimer formation, but its precise biological role remains to be discovered.The active site of the catalytic domain of GBBH is similar to that of other 2KG oxygenases, and Fe(II)-binding residues form a conserved His-X-Asp-Xn-His triad, which is found in all related enzymes.
Keywords:GBBH  gamma-butyrobetaine hydroxylase  GBB  gamma-butyrobetaine  2KG  2-ketoglutarate  DBSH  double-stranded β-helix
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