Slow-onset feedback inhibition: inhibition of Mycobacterium tuberculosis alpha-isopropylmalate synthase by L-leucine.
This report describes the first demonstration of slow-onset feedback inhibition of an enzyme that catalyzes the first committed step in a biosynthetic pathway. alpha-Isopropylmalate synthase (IPMS) catalyzes the first committed step of the l-leucine biosynthetic pathway and is feedback-inhibited by l-leucine. Initial velocity experiments on the Mycobacterium tuberculosis IPMS indicate that inhibition by l-leucine is linearly noncompetitive versus alpha-ketoisovalerate. Time-courses displayed a burst of product formation followed by a linear steady-state rate when reactions were initiated by the addition of enzyme. The burst rate showed a hyperbolic dependence on the concentration of l-leucine indicating that inhibition proceeds in two steps, an initial rapid binding step followed by slow isomerization to a more tightly bound complex.
de Carvalho
Luiz P S
LP
Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York, 10461, USA.
Argyrou
Argyrides
A
Blanchard
John S
JS
D015079:2-Isopropylmalate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D025461:Feedback, Physiological; D007700:Kinetics; D007930:Leucine / Q000737:chemistry* / Q000494:pharmacology*; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D013997:Time Factors
D015079:2-Isopropylmalate Synthase; D007930:Leucine