Professor
Department of Biological Chemistry
School of Medicine

ppederse@jhmi.edu

400 Biophysics Building
725 N. Wolfe Street
Baltimore, MD 21205

Office: 410-955-3827
Lab: 410-955-3167

This laboratory is interested in cell energetics and the relationship of cell energetics to molecular medicine and disease. Both mitochondrial and glycolytic processes are being studied at the tissue, cell, and molecular level. Also, the relationship of these processes to the diseases cancer and heart disease, the two major causes of death in the U.S. are being studied with the objective of discovering and developing new therapies. Specific projects in the laboratory that are currently under investigation are the following:

The structure, mechanism, and regulation of the mitochondrial ATP synthase/ATPase complex. Recently we have shown that in mitochondria the ATP synthase is in complex formation with two transport systems, the adenine nucleotide carrier (ANC) and the phosphate carrier (PIC). This ATP synthase/ANC/PIC complex has been named by us the “ATP synthasome” and is being studied structurally and functionally, and also as a target site for anticancer drugs. Recently we solved the 3-dimensional structure of a transition-like state of the catalytic unit of the ATP synthase, and would now like to obtain a 3-D structure for the complete ATP synthasome complex.

The molecular basis of cancer’s most common phenotype, i.e., an elevated glucose metabolism. Emphasis here is on hexokinase II (HKII), the first enzyme of glucose catabolism, and also an anti-cell death protein. We are particularly interested in better understanding the regulation of the gene that encodes HKII as it is markedly overexpressed in many human cancers. We are interested also in screening for new therapies that target HKII and destroy cancer cells while sparing normal cells. Recently, a small chemical compound (3-bromppyruvate) that attacks both the ATP synthasome and HKII was found to be a potent inhibitor of advanced cancers growing in experimental animals. The cancers were eradicated and the animal lived out a normal life span.

The regulation of heart function under normal and ischemic conditions as it relates to the mitochondrial ATP synthase/ATPase complex. When oxygen to the heart becomes limiting there are a number of changes that take place as it relates to the heart’s major energy producer the mitochondria. Several of these changes involve the binding or de-binding of key peptide regulators to the mitochondrial ATP synthase while others involved covalent phosphorylation or de-phosphorylation of this critical enzyme. Currently, we are trying to understand which regulatory events become most important as oxygen to the heart (e.g., like in a heart attack) becomes limiting (ischemic conditions). We are interested also in solving the 3-dimensional structure of the ATP synthasome of heart with and without these regulators.

Selected Publications
Chen, C., A.K. Saxena, W.N. Simcoke, D.N. Garboczi, P.L. Pedersen, and Y.H. Ko. (2006) Mitochondrial ATP synthase: Crystal structure of the catalytic F1 Unit in a vanadate-induced transition state and implications for mechanism. J. Biol. Chem. 281:13777-13783.

Pedersen, P.L. (2005) Transport ATPases: Structure, Motors, Mechanism and Medicine. J. Bioenerg. Biomemb. 37:349 -357.

Chen, C., Y.H. Ko, M. Delannoy, S.J. Ludtke, W. Chiu, and P.L. Pedersen. (2004) Mitochondrial ATP synthasome: Three dimensional structure by electron microscopy of the ATP synthase in complex formation with carriers for Pi and ADP/ATP. J. Biol. Chem. 279:31761-31768.

Lee, M.G. and P.L. Pedersen. (2003) Glucose metabolism in cancer: Importance of transcription factor-DNA interactions within a short segment of the proximal region of the type II hexokinase promoter. J. Biol. Chem. 278:41047-41058.

Hong, S., and P.L. Pedersen. (2003) ATP synthases: Insights into their motor functions from sequence and structural analyses. J. Bioenerg. Biomemb. 35:95-120.

Ko, Y.H., M. Delannoy, J. Hullihen, W. Chiu and P.L. Pedersen. (2003) Mitochondrial ATP synthasome. Cristae-enriched membranes and a multiwell detergent screening assay yield dispersed single complexes containing the ATP synthase and carriers for Pi and ADP/ATP. J. Biol. Chem. 278:12305-12309.

Goel, A., S.P. Mathupala and P.L. Pedersen. (2003) Glucose catabolism in cancer cells: The CpG island of the rat type II hexokinase gene is differentially methylated in normal liver and hepatoma cells. J. Biol. Chem. 278:15333-15334.

Hong, S. and P.L. Pedersen. (2003) Subunit E of mitochondrial ATP synthase: A bioinformatic analyses reveals a phosphopeptide binding motif supporting a multifunctional regulatory role and identifies a related human brain protein with the same motif. Proteins: Struc. Funct. Genet. 51:155-161.