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Order and disorder in mitochondrial aldehyde dehydrogenase
T D Hurley1, S Perez-Miller, H Breen
1Department of Biochemistry and Molecular Biology, Program in Medical Biophysics, Indiana University School of Medicine, 635 Barnhill Drive, 46202-5122, Indianapolis, IN, USA. thurley@iupui.edu
Chemico-Biological Interactions
|April 18, 2001
Summary
Mitochondrial aldehyde dehydrogenase (ALDH2) exhibits half-of-the-sites reactivity, suggesting communication between active sites. Structural studies reveal coenzyme binding induces order-to-disorder transitions, potentially explaining negative cooperativity in ALDH2.
Area of Science:
- Biochemistry
- Structural Biology
- Enzymology
Background:
- Mitochondrial aldehyde dehydrogenase (ALDH2) displays half-of-the-sites reactivity, a phenomenon often described as extreme negative cooperativity.
- This implies a communication pathway exists between enzyme active sites to transmit structural changes upon ligand binding.
Purpose of the Study:
- To investigate the structural basis for half-of-the-sites reactivity and negative cooperativity in human ALDH2.
- To elucidate the mechanism of communication between ALDH2 subunits.
Main Methods:
- X-ray crystallography was used to determine the structures of wild-type ALDH2 (apo-enzyme and NADH complex) and an R475Q mutant (apo-enzyme).
- Comparison of four different ALDH2 structures, including a previously published ALDH2-NAD(+) complex.
Main Results:
- Coenzyme binding to ALDH2 induces a disorder-to-order transition in residues surrounding the adenosine-binding site.
- The R475Q mutant exhibits positive cooperativity, with elevated thermal parameters in apo-enzyme state indicating disorder.
- Subunit interface interactions involving residues 246-262 may mediate communication.
Conclusions:
- Structural changes upon coenzyme binding, particularly at the subunit interface, likely mediate communication and explain negative cooperativity in ALDH2.
- The R475Q mutation alters this communication, leading to positive cooperativity, supporting the proposed mechanism.
- Further research will explore the link to the E487K allelic variant.