Lee McAlister-Henn, PhD, Professor and Deputy Chair
|Education:||Ph.D. (1980) UT Southwestern Medical Center, Dallas|
|Post Doctoral:||University of Connecticut, Farmington|
University of California, Davis
|Other Faculty Positions:||Assistant/Associate Professor,|
School of Medicine
University of California, Irvine
Allosteric Regulation of Energy Metabolism and Cellular Sources of NADPH for Antioxidant Function
Research in this laboratory uses molecular genetic approaches to analyze regulation of the intracellular redox environment. (A) A major area of investigation is the regulation of rates of oxidative metabolism at the level of allosteric regulation of mitochondrial NAD-specific isocitrate dehydrogenase (IDH), which catalyzes a rate-limiting step in the TCA cycle. We are constructing mutant forms of the enzyme in yeast to investigate the extent and importance of allosteric regulation in vivo. We are also investigating the X-ray crystallographic structure of the enzyme (see Figure), which serves as an excellent model for the co-evolution of regulatory and catalytic ligand-binding sites and for fundamental principles involved in allostery. [This work is supported by NIH grant GM051265.] (B) In another major area, we have focused on two essential cytosolic sources of NADPH (the hexose monophosphate pathway and cytosolic NADP-specific isocitrate dehydrogenase). Loss of both these sources results in a rapid decrease in viability of yeast cells under conditions when metabolic flux through the pathways of peroxisomal-oxidation or of mitochondrial respiration is increased. This decrease in viability is due to the accumulation of deleterious byproducts of these endogenous metabolic pathways due to inadequate production of NADPH for protective antioxidant enzyme systems. We have determined endogenous macromolecular targets of endogenous oxidative metabolic byproducts. [This work is supported by NIH grant AG017477.] (C) In both these areas of investigation, we have developed techniques to quantify levels of various cellular metabolites and of reduced and oxidized forms of NAD(P) cofactors. These measurements have led to an understanding of dramatic and rapid changes that can occur in the cellular redox environment, and they have led to major new hypotheses related to signaling events that control rates of flux through central metabolic pathways and to the impact of changes in metabolic flux to the extension of life span.
- Ligand binding and structural changes associated with allostery in yeast NAD(+)-specific isocitrate dehydrogenase.
Arch Biochem Biophys: 2012-03-15; 519(2); 112-7 Epub: 2011-10-07.
PMID: 22008468   LINK:
- Effects of excess succinate and retrograde control of metabolite accumulation in yeast tricarboxylic cycle mutants.
Lin AP, Anderson SL, Minard KI, McAlister-Henn L
J Biol Chem: 2011-09-30; 286(39); 33737-46 Epub: 2011-08-12.
PMID: 21841001   LINK:
- Basis for half-site ligand binding in yeast NAD(+)-specific isocitrate dehydrogenase.
Lin AP, McAlister-Henn L
Biochemistry: 2011-09-27; 50(38); 8241-50 Epub: 2011-08-30.
PMID: 21861471   LINK:
- Construction and analyses of tetrameric forms of yeast NAD+-specific isocitrate dehydrogenase.
Lin AP, Demeler B, Minard KI, Anderson SL, Schirf V, Galaleldeen A, McAlister-Henn L
Biochemistry: 2011-01-18; 50(2); 230-9 Epub: 2010-12-21.
PMID: 21133413   LINK:
- Pnc1p supports increases in cellular NAD(H) levels in response to internal or external oxidative stress.
Minard KI, McAlister-Henn L
Biochemistry: 2010-08-03; 49(30); 6299-301
PMID: 20590162   LINK:
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