Mahin D. Maines Professor of Biochemistry & Biophysics, and Environmental Medicine B.A. 1964 (Ball State University) Ph.D. 1970 (University of Missouri) Burroughs Wellcome Toxicology Scholar NIH Merit Awardee (E-Mail: mahin_maines@urmc.rochester.edu)

The heme molecule is the active moiety of all cytochromes and globins; the cellular concentration of heme is regulated by the heme oxygenase system. We have identified two forms of heme oxygenase, HO-1 and HO-2. The two forms exhibit marked differences in molecular properties and are products of two different genes. HO-1 is a heat shock protein (hsp32) and highly inducible by oxidative stress. HO-2 is prominently and constitutively expressed in the brain and testes. The products of heme oxygenase activity are biologically active: carbon monoxide is a newly identified signaling molecule, which functions as nitric oxide in generation of cGMP; iron regulates the expression of certain genes, including ferritin and transferrin and NO synthase; and biliverdin is an effective antioxidant and antiviral complex. Biliverdin is reduced to bilirubin, also an antioxidant and anti-complement compound, by biliverdin reductase, a zinc finger protein, which is unique by virtue of having a dual co-factor/dual pH requirement.

Current research includes the following: molecular and genetic analysis of regulation and control of expression of heme oxygenase isozymes, using transgenic mice; examination of the role of carbon monoxide in generation of cGMP in the brain; and, the consequence of modulation of heme oxygenase activity on NO synthase--/guanylate cyclase cascade; characterization of biliverdin reductase structure and function; and the investigation of whether the reductase is a transcriptional factor.

Recent Publications

Ewing JF, Maines MD. 2006. Regulation and expression of heme oxygenase enzymes in aged-rat brain: age related depression in HO-1 and HO-2 expression and altered stress-response. J Neural Transm. Apr;113(4):439-454.

Maines MD. 2005. The heme oxygenase system: update 2005. Antioxid Redox Signal. Nov-Dec;7(11-12):1761-1766. Review.

Maines MD. 2005. New insights into biliverdin reductase functions: linking heme metabolism to cell signaling. Physiology (Bethesda). Dec;20:382-9. Review.

Maines MD, Gibbs PE. 2005. 30 some years of heme oxygenase: From a "molecular wrecking ball" to a "mesmerizing" trigger of cellular events. Biochem Biophys Res Commun. Sep 22; [Epub ahead of print]

Lerner-Marmarosh N, Shen J, Torno MD, Kravets A, Hu Z, Maines MD. 2005. Human biliverdin reductase: a member of the insulin receptor substrate family with serine/threonine/tyrosine kinase activity. Proc Natl Acad Sci U S A. May 17;102(20):7109-7114.

Miralem T, Hu Z, Torno MD, Lelli KM, Maines MD. 2005. Small interference RNA-mediated gene silencing of human biliverdin reductase, but not that of heme oxygenase-1, attenuates arsenite-mediated induction of the oxygenase and increases apoptosis in 293A kidney cells. J Biol Chem. Apr 29;280(17):17084-17092

Kravets A, Hu Z, Miralem T, Torno MD, Maines MD. 2004. Biliverdin reductase, a novel regulator for induction of activating transcription factor-2 and heme oxygenase-1. J Biol Chem. May 7;279(19):19916-23.

Mayer RD, Wang X, Maines MD. 2003. Nitric Oxide Inhibitor N{omega}-Nitro-L-arginine Methyl Ester Potentiates Induction of Heme Oxygenase-1 in Kidney Ischemia/Reperfusion Model: A Novel Mechanism for Regulation of the Oxygenase. J Pharmacol Exp Ther. Jul;306(1):43-50.

Wang X, Hauptmann N, Taylor E, Foreman M, Khawli LA, Maines MD. 2003. Neo trofin increases heme oxygenase-1 selectively in neurons. Brain Res. Feb 7;962(1-2):1-14.

Maines MD. 2003. Bile pigments: newcomers to the cell signaling arena. Toxicol Sci. Jan;71(1):9-10. Review.

Whitby FG, Phillips JD, Hill CP, McCoubrey W, Maines MD. 2002. Crystal structure of a biliverdin IXalpha reductase enzyme-cofactor complex. J Mol Biol. Jun 21;319(5):1199-1210.

Maines MD. Heme oxygenase 1 transgenic mice as a model to study neuroprotection. 2002. Methods Enzymol. 353:374-388.

Ahmad Z, Salim M, and Maines MD. 2002. Human biliverdin reductase is a leucine zipper-like DNA-binding protein and functions in transcriptional activation of heme oxygenase-1 by oxidative stress. J Biol Chem. Mar 15;277(11):9226-9232.