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		Search Text: Home/< Back ToThe Science/Biochemistry
  Biochemistry
    The Laboratory of Biochemistry, led by Dr. Rodney L. Levine, focusses its research on the identification and cellular effects of oxidative modifications of proteins. These modifications serve to control oxidative stress, regulate cellular function, and modulate protein structure.
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  Rodney Levine, M.D., Ph.D.
          Senior Investigator
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      Meet the Team
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  Senior Investigator Research Interests
            
  Research Interests
              Because eukaryotic cells depend on molecular oxygen for normal metabolism, they generate reactive oxygen species (ROS) that can cause multiple forms of cellular stress and damage. For several years, Dr. Levine has focused his research on the identification of oxidative modifications of proteins. He is interested in the conditions that give rise to modifications in which amino acids are modified, and the impact those modifications have on enzymatic function or structural integrity.

Several years ago, in collaboration with the late Earl Stadtman, Dr. Levine discovered a novel form of protein modification—carbonylation—that is now a widely accepted measure of oxidative modification in cells ranging from bacteria to humans. Carbonylation is typically associated with protein dysfunction. In a variety of species, carbonyl content rises dramatically in the last third of an organism’s life and may be causally related to the phenotypic changes of aging. Although reactive oxygen species are usually promiscuous in their reactivity, Dr. Levine and his colleagues found that this modification was localized to the metal binding sites of proteins that contained them. Such binding sites normally recruit Mg2+, Mn2+, or Ca2+, but upon binding of Fe3+, the protein was rendered vulnerable to ROS modifications and loss of the metal binding site.

Dr. Levine has focused on oxidative modifications that are specific to methionine residues. This amino acid is particularly vulnerable to oxidation. Virtually every aerobic organism has at least one enzyme (methionine sulfoxide reductase) that functions to reduce oxidized methionine back to its original form. To study these modifications, Dr. Levine’s laboratory is using a variety of techniques from biochemistry and mass spectrometry to transgenic mouse models with altered enzymatic activity of the reductases.

Based on his research, Dr. Levine proposed the concept that methionines serve an important role as an antioxidant, both for the proteins in which they reside and the cell itself. Counter to the commonly held notion that methionines (which are hydrophobic residues) are typically buried within proteins, many methionine residues lie on the surfaces of proteins. Much like well-known antioxidant molecules such as vitamins E and C, these exposed methionines intercept ROS and become oxidized. In this context, methionine sulfoxide reductase operates to bring the antioxidant system full circle.

More recently, Dr. Levine and his colleagues have found that methionine sulfoxide reductase catalyzes oxidation and reduction of methionine residues bidirectionally. This finding opens the door to a role for oxidative modification of methionine as a cellular signaling mechanism. Whereas ROS production has been viewed as uniformly deleterious to cellular function, it is now clear that cells actually require a certain level of oxidants for optimal function. Dr. Levine is pursuing the hypothesis that oxidative modifications of proteins are not always a negative effect of stress, but also participate in normal cellular signaling.
  Featured Publications
                MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII.
            Authors:Konstantinidis K, Bezzerides VJ, Lai L, Isbell HM, Wei AC, Wu Y, Viswanathan MC, Blum ID, Granger JM, Heims-Waldron D, Zhang D, Luczak ED, Murphy KR, Lu F, Gratz DH, Manta B, Wang Q, Wang Q, Kolodkin AL, Gladyshev VN, Hund TJ, Pu WT, Wu MN, Cammarato A, B
                                                                                                                        
            J Clin Invest.
      
                2020 Sep 01;130(9):4663-4678
        Read Publication
                      Loss of methionine sulfoxide reductases increases resistance to oxidative stress.
            Authors:Lai L, Sun J, Tarafdar S, Liu C, Murphy E, Kim G, Levine RL
                                                                                            
            Free Radic Biol Med
      
                2019 Dec 01;145:374-384
        Read Publication
                      Methionine in Proteins: It's Not Just for Protein Initiation Anymore.
            Authors:Lim JM, Kim G, Levine RL.
                                                                                                                        
            Neurochem Res.
      
                2019 Jan 01;44(1):247-257
        Read Publication
                      Oxidative stress-induced autonomous activation of the calcium/calmodulin-dependent kinase II involves disulfide formation in the regulatory domain.
            Authors:Rocco-Machado N, Lai L, Kim G, He Y, Luczak ED, Anderson ME, Levine RL.
                                                                                                                        
            J Biol Chem.
      
                2022 Nov 01;298(11):102579
        Read Publication
                      Response to oxidative stress of AML12 hepatocyte cells with knockout of methionine sulfoxide reductases.
            Authors:Trujillo-Hernandez JA, Levine RL.
                                                                                            
            Free Radic Biol Med.
      
                2023 Aug 20(205):100-106
        Read Publication
                                View More Publications
  Meet the Team

    profile

            Rodney Levine, M.D., Ph.D.
                Senior Investigator
                Rodney Levine graduated from Stanford University with a B.S. in chemistry and an A.B. in biology in 1968 and earned his M.D. and Ph.D. in physiology from Stanford in 1973. He completed his residency in pediatrics at the University of Colorado Medical Center in 1975 and his fellowship in perinatal medicine at the University of Colorado Medical Center and Denver Children’s Hospital in 1977. He joined the NHLBI in 1977 as a research associate and rose to become Chief of the Laboratory of Biochemistry in 2008. He is board certified in pediatrics and in neonatal-perinatal medicine and is professor emeritus at the Uniformed Services University of the Health Sciences. Dr. Levine has authored or coauthored more than 200 papers. He holds memberships with the American Association for the Advancement of Science, American Pediatric Society, American Society for Biochemistry and Molecular Biology, and Society for Free Radical Biology which has named him a Fellow of the Society.
    
          Contact the lab
    50 South DrBethesda, MD 20814United States
        Phone:
                    301-496-2310
                Fax:
  Kim
    
            George  Kim, Ph.D.
        

    Staff Scientist

        kimg@nhlbi.nih.gov
            Lim
    
            Jungmi Lim
        

    Research Fellow

        jungmi.lim@nih.gov
            Nathalia
    
            Nathália  Rocco  Machado, Ph.D.
        

    Postdoctoral Fellow
            José
    
            José Abraham Trujillo Hernandez, Ph.D.
        

    Postdoctoral Fellow Back To Top Link
  

        

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