3FMI

Crystal structure of Mycobacterium tuberculosis dethiobiotin synthetase complexed with 7-Keto 8-aminopelargonic acid

Summary for 3FMI

• Entry DOI: 10.2210/pdb3fmi/pdb
• Related: 3FGN 3FMF
• Descriptor: Dethiobiotin synthetase, SULFATE ION, 7-KETO-8-AMINOPELARGONIC ACID, ... (4 entities in total)
• Functional Keywords: rv1570, biod, ligase, atp-binding, biotin biosynthesis, magnesium, nucleotide-binding
• Biological source: Mycobacterium tuberculosis
• Cellular location: Cytoplasm (By similarity): O06620
• Total number of polymer chains: 4
• Total formula weight: 102273.52

Authors

Dey, S.,Sacchettini, J.C. (deposition date: 2008-12-22, release date: 2009-06-30, Last modification date: 2023-09-06)

Primary citation

Dey, S.,Lane, J.M.,Lee, R.E.,Rubin, E.J.,Sacchettini, J.C.
Structural characterization of the Mycobacterium tuberculosis biotin biosynthesis enzymes 7,8-diaminopelargonic acid synthase and dethiobiotin synthetase .
Biochemistry, 49:6746-6760, 2010

PubMed Abstract: Mycobacterium tuberculosis (Mtb) depends on biotin synthesis for survival during infection. In the absence of biotin, disruption of the biotin biosynthesis pathway results in cell death rather than growth arrest, an unusual phenotype for an Mtb auxotroph. Humans lack the enzymes for biotin production, making the proteins of this essential Mtb pathway promising drug targets. To this end, we have determined the crystal structures of the second and third enzymes of the Mtb biotin biosynthetic pathway, 7,8-diaminopelargonic acid synthase (DAPAS) and dethiobiotin synthetase (DTBS), at respective resolutions of 2.2 and 1.85 A. Superimposition of the DAPAS structures bound either to the SAM analogue sinefungin or to 7-keto-8-aminopelargonic acid (KAPA) allowed us to map the putative binding site for the substrates and to propose a mechanism by which the enzyme accommodates their disparate structures. Comparison of the DTBS structures bound to the substrate 7,8-diaminopelargonic acid (DAPA) or to ADP and the product dethiobiotin (DTB) permitted derivation of an enzyme mechanism. There are significant differences between the Mtb enzymes and those of other organisms; the Bacillus subtilis DAPAS, presented here at a high resolution of 2.2 A, has active site variations and the Escherichia coli and Helicobacter pylori DTBS have alterations in their overall folds. We have begun to exploit the unique characteristics of the Mtb structures to design specific inhibitors against the biotin biosynthesis pathway in Mtb.

PubMed: 20565114
DOI: 10.1021/bi902097j

Experimental method

X-RAY DIFFRACTION (2.18 Å)