Home Faculty and Research Faculty by Name Michael Marletta

Michael Marletta

Aldo DeBenedictis Distinguished Professor of Chemistry and Professor of Biochemistry and Molecular Biology

Lab Homepage: http://www.cchem.berkeley.edu/mmargrp/

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Research Interests

Research in this laboratory is focused on structure/function relationships in proteins with a particular emphasis on the catalytic and biological properties of enzymes. Current emphasis is on nitric oxide signaling (including studies on nitric oxide synthase, guanylate cyclase and S-nitrosation mechanisms), oxygen sensing, iron regulatory mechanisms, and unique biochemical pathways in parasites such as Plasmodium falciparum.

Current Projects

Cellular signaling with NO typically acts in paracrine fashion, where one cell that makes NO signals an adjacent target cell. NO is both toxic and chemically reactive, properties that argue against a key role in signaling. It is freely diffusible, and the chemical instability of NO leads to a cellular messenger whose signal lifetime is dictated by this instability. NO stimulates the synthesis of guanosine 3':5'-cyclic monophosphate, (cGMP) in a target cell by directly activating the soluble isoform of guanylate cyclase (sGC). Constitutive isoforms of NOS make NO for signaling. The immune system, on the other hand, uses NO to kill or inhibit the growth of pathogens, generated via the inducible isoform of NOS.

In studies directed toward a molecular understanding on NO signaling, we found homlogues of the sGC heme domain in a number of prokaryotes. Some of these heme domains share properties with sGC (they do not bind oxygen), while others do bind oxygen. We have termed this new family of heme-based sensor proteins H-NOX proteins (for Heme-Nitric oxide OXygen). In collaboration with the Kuriyan lab we have solved a crystal structure of one member of the family. This structure and subsequent functional studies have uncovered how Nature is able to selectively sense similar ligands such as NO and oxygen.

Nitric Oxide Synthase. NOS catalyzes the conversion of L-arginine to NO and citrulline. NOS contains two tightly bound flavin cofactors that deliver reducing equivalents to a cytochrome P-450-type heme. The enzyme also contains a tightly bound pterin cofactor. The mechanism leading to NO formation is complicated and the design of selective inhibitors rests, in part, on mechanism. Our studies to date have involved various aspects of structure and catalysis, and future investigations will continue to explore these areas.

Soluble Guanylate Cyclase. NO activation of sGC and the mechanism to turn the enzyme off are key questions under study. The heme moiety on sGC is an excellent trap for NO because nitrosyl-heme complexes form rapidly. However, it is not obvious how catalytic activity and the resulting signal (cGMP) would be turned off, given that nitrosyl-heme complexes are generally very stable. Our work to date, mainly via spectroscopic methods, has shown that the heme in sGC is unlike any characterized previously and is finely tuned to interact with NO in a way that allows for transient signaling via transient activation of the enzyme. We are working toward a detailed understanding of this control because therein lies the crucial pharmacology. Structural studies in collaboration with the Kuriyan group are underway. Tolerance to nitrovasodilator drugs such as nitro-glycerin is clinically very important. We are exploring the hypothesis that tolerance is brought about by desensitation of sGC to NO.

Cellular NO Targets. Little is known about NO action in the host response to infection and in the response of pathogens to NO. In fact, some pathogens such as Mycobacterium tuberculosis, are resistant to NO. We are studying the diphtheria toxin repressor protein (DtxR) and the ferric uptake regulator (Fur) as models for NO action. This work has been extended to include collaborative studies with the Rine lab and novel genes involved in iron regulation.

Malaria Biochemistry. In our search for novel metabolic pathways and reactions in the parasite Plasmodium falciparum, we are exploring the mechanism of hemozoin formation, specifically looking at the histidine-rich proteins as a novel class of heme-binding proteins.

Selected Publications

Gray, J.M., Karow, D.S., Lu, H., Chang, J.S., Marletta, M.A., Bargmann, C.I. (2004). Oxygen sensation and social feeding mediated by a C. elegans guanylate cyclase homologue.  Nature 430: 317-322.  

Karow, D.S., Pan, D., Pellicena, P., Presley, A., Mathies, R.A. and Marletta, M.A. (2004). Spectroscopic characterization of the sGC-like heme domains from Vibrio cholerae and Thermoanaerobacter tengcongensis.  Biochemistry 43: 10203-10211.  

Pellicena, P., Karow, D.S., Marletta, M.A. and Kuriyan, J. (2004).  Crystal structure of an oxygen binding domain related to soluble guanylate cyclase.  Proc. Natl. Acad. Sci. USA 101: 12854-12859.

Winger, J.A. and Marletta, M.A. (2005).  Expression and characterization of the catalytic domains of soluble guanylate cyclase: interaction with the heme domain.  Biochemistry 44: 4083-4090.

Mitchell, D.A., Erwin, P.A., Michel, T. and Marletta, M.A. (2005).  S-Nitrosation and regulation of inducible nitric oxide synthase.  Biochemistry 44: 4636-4647.

Boon, E.M., Huang, S.H. and Marletta, M.A. (2005). A molecular basis for NO selectivity in soluble guanylate cyclase.  Nature Chemical Biology 1: 53-59.

Luzzi, S.D. and Marletta, M.A. (2005). L-Arginine analogs as alternate substrates for nitric oxide synthase.  Bioorganic Medicinal Chemistry Letters 15: 3934-3941.

Mitchell, D.A. and Marletta, M.A. (2005). Thioredoxin catalyzes the S-nitrosation of the caspase-3 active site cysteine.  Nature Chemical Biology 1: 154-158.

Mills, S.A. and Marletta, M.A. (2005). Metal binding characteristics and the role of iron oxidation in the ferric uptake regulator from Escherichia coli.  Biochemistry 44: 13553-13559.

Cary, S.P.L., Winger, J.A. and Marletta, M.A. (2005). Tonic and acute nitric oxide signaling through soluble guanylate cyclase is mediated by non-heme NO, ATP, and GTP.  Proc. Natl. Acad. Sci. USA 102: 13064-13069.  

Boon, E. M. and Marletta, M. A. (2005). Ligand discrimination in soluble guanylate cyclase and the H-NOX family of heme sensor proteins.  Curr. Opin. Chem. Biol. 9: 441-446.  

Derbyshire, E.A., Tran, R., Mathies, R.A. and Marletta, M.A. (2005). Characterization of Nitrosoalkane Binding and Activation of Soluble Guanylate Cyclase.  Biochemistry 44: 16257-16265.  

Karow, D.S., Pan, D., Davis, J.H., Behrends, S., Mathies, R.A., and Marletta, M.A. (2005) Characterization of Functional Heme Domains from Soluble Guanylate Cyclase.  Biochemistry 44: 16266-16274.  

Hering, K.W., Artz, J.D., Pearson, W.H. and Marletta, M.A. (2006). The Design and Synthesis of YC-1 Analogues as Probes for Soluble Guanylate Cyclase.  Bioorg. Med. Chem Letters 16: 618-621.  

Cary, S.P.L., Winger, J.A., Derbyshire, E.R. and Marletta, M.A. (2006). Nitric oxide signaling: no longer simply on or off. TIBS 31: 231-239.

Erwin P.A., Mitchell D.A., Sartoretto J., Marletta M.A. and Michel T. (2006).  Subcellular targeting and differential S-nitrosylation of endothelial nitric-oxide synthase.  J. Biol. Chem. 281: 151-157.

Boon, E.A., Davis, J.H., Tran, R., Karow, D.S., Huang, S.H., Pan, D., Miazgowicz, M.M., Mathies, R.A. and Marletta, M.A. (2006) Nitric oxide binding to prokaryotic homologs of the soluble guanylate cyclase β1 H-NOX domain.  J. Biol. Chem. 281:21892-21902.  

Martin, N.I. and Marletta, M.A. (2006) NG  -Hydroxyguanidines from Primary Amines. Organic Letters 8:4035-4038.

Niles, J.C. and Marletta, M.A. (2006). Utilizing RNA Aptamers to Probe a Physiologically Important Heme-Regulated Cellular Network. ACS Chemical Biology 1:515-524.  

Chang, A.J., Chronis, N., Karow, D.S., Marletta, M.A. Bargmann, C.I. (2006). A Distributed Chemosensory Circuit for Oxygen Preference in C. elegans.  PLOS Biology 4(9): e274.  

Mitchell, D.A., Morton, S.U. and Marletta M. A. (2006). Design and characterization of an active site selective caspase-3 transnitrosating agent. ACS Chemical Biology 1:659-665.

Woodward, J.J., Martin, N.I. and Marletta, M.A. (2007). An Escherichia coli expression-based method for heme substitution.  Nature Methods 4: 43-45.   

Winger, J.A. Derbyshire, E.R. and Marletta, M.A. (2007) Dissociation of Nitric Oxide from Soluble Guanylate Cyclase and H-NOX Domain Constructs.  Journal of Biological Chemistry 282: 897-207.

Last Updated 2007-02-13