5TE2

Crystal structure of 7,8-diaminopelargonic acid synthase (BioA) from Mycobacterium tuberculosis, complexed with a mechanism-based inhibitor

Summary for 5TE2

• Entry DOI: 10.2210/pdb5te2/pdb
• Related: 3TFT 3TFU 4CXQ
• Descriptor: Adenosylmethionine-8-amino-7-oxononanoate aminotransferase, [5-hydroxy-4-({[6-(3-hydroxypropyl)-4-oxo-1,4-dihydropyridin-3-yl]amino}methyl)-6-methylpyridin-3-yl]methyl dihydrogen phosphate, DI(HYDROXYETHYL)ETHER, ... (6 entities in total)
• Functional Keywords: inhibitor complex, transaminase, plp, transferase, transferase-inhibitor complex, mechanism-based inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mycobacterium bovis (strain ATCC BAA-935 / AF2122/97)
• Total number of polymer chains: 2
• Total formula weight: 98190.07

Authors

Maize, K.M.,Eiden, C.,Aldrich, C.C.,Finzel, B.C. (deposition date: 2016-09-20, release date: 2017-05-31, Last modification date: 2023-10-04)

Primary citation

Eiden, C.G.,Maize, K.M.,Finzel, B.C.,Lipscomb, J.D.,Aldrich, C.C.
Rational Optimization of Mechanism-Based Inhibitors through Determination of the Microscopic Rate Constants of Inactivation.
J. Am. Chem. Soc., 139:7132-7135, 2017

PubMed Abstract: Mechanism-based inhibitors (MBIs) are widely employed in chemistry, biology, and medicine because of their exquisite specificity and sustained duration of inhibition. Optimization of MBIs is complicated because of time-dependent inhibition resulting from multistep inactivation mechanisms. The global kinetic parameters k and K have been used to characterize MBIs, but they provide far less information than is commonly assumed, as shown by derivation and simulation of these parameters. We illustrate an alternative and more rigorous approach for MBI characterization through determination of the individual microscopic rate constants. Kinetic analysis revealed the rate-limiting step of inactivation of the PLP-dependent enzyme BioA by dihydro-(1,4)-pyridone 1. This knowledge was subsequently applied to rationally design a second-generation inhibitor scaffold with a nearly optimal maximum inactivation rate (0.48 min).

PubMed: 28510452
DOI: 10.1021/jacs.7b00962

Experimental method

X-RAY DIFFRACTION (1.8 Å)