Fellutamide B is a Potent Inhibitor of the Mycobacterium tuberculosis Proteasome

Journal Article · Fri Jan 01 04:00:00 EST 2010 · Archives of Biochemistry and Biophysics

DOI:https://doi.org/10.1016/j.abb.2010.06.009· OSTI ID:1019724

Lin, G; Li, D; Chidawanyika, T; Nathan, C; Li, H

Via high-throughput screening of a natural compound library, we have identified a lipopeptide aldehyde, fellutamide B (1), as the most potent inhibitor of the Mycobacterium tuberculosis (Mtb) proteasome tested to date. Kinetic studies reveal that 1 inhibits both Mtb and human proteasomes in a time-dependent manner under steady-state condition. Remarkably, 1 inhibits the Mtb proteasome in a single-step binding mechanism with K{sub i} = 6.8 nM, whereas it inhibits the human proteasome {beta}5 active site following a two-step mechanism with K{sub i} = 11.5 nM and K*{sub i} = 0.93 nM. Co-crystallization of 1 bound to the Mtb proteasome revealed a structural basis for the tight binding of 1 to the active sites of the Mtb proteasome. The hemiacetal group of 1 in the Mtb proteasome takes the (R)-configuration, whereas in the yeast proteasome it takes the (S)-configuration, indicating that the pre-chiral CHO group of 1 binds to the active site Thr1 in a different orientation. Re-examination of the structure of the yeast proteasome in complex with 1 showed significant conformational changes at the substrate-binding cleft along the active site. These structural differences are consistent with the different kinetic mechanisms of 1 against Mtb and human proteasomes.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: DOE - OFFICE OF SCIENCE
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 1019724
• Report Number(s): BNL--95570-2011-JA
• Journal Information: Archives of Biochemistry and Biophysics, Journal Name: Archives of Biochemistry and Biophysics Journal Issue: 2 Vol. 501; ISSN ABBIA4; ISSN 0003-9861
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS
CONFORMATIONAL CHANGES
ENZYMES
KINETICS
MYCOBACTERIUM TUBERCULOSIS
ORIENTATION
PEPTIDES
STEADY-STATE CONDITIONS
YEASTS
national synchrotron light source