PETER L. PEDERSEN, PH.D.
Professor
The Johns Hopkins University School of Medicine
Department of Oncology
Sidney Kimmel Cancer Institute (Member)
Center for Obesity Research and Metabolism (Member)

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Dr. Pedersen was born in Muskogee, Oklahoma as the son of a strawberry farmer and a chemistry teacher. In 1961, he graduated from the University of Tulsa with a B.S. in Chemistry. In three short years, he would go on to graduate from the University of Arkansas with a Ph.D. in Chemistry. That year he journeyed to The Johns Hopkins University School of Medicine to do a Postdoctoral Fellowship under the watchful eye of Dr. Albert L. Lehninger in the Department of Physiological Chemistry.

In 1967, he was appointed to the position of Instructor in the same department, and within a year was promoted to Assistant Professor. In 1972, he was appointed to Associate Professor and was named Professor three years later. He has since held this position to the current date, assisting 22 graduate students and 32 postdoctoral fellows in their studies at the institution.

Dr. Pedersen has been an active educator during his tenure, instructing such courses as: Preclinical Sciences, Biochemistry, and Metabolism to the medical students in the School of Medicine. In doing so, he has received countless awards recognizing his important role in the preclinical coursework.

Dr. Pedersen been the recipient of numerous NIH grants since his postdoctoral fellowship, in 1964. This includes his award of the NIH Fogarty Scholar in Residence at the NCI from 1992-1993. For the past 25 years, he has been rated above the 95th percentile of the districution of extramural NIH grants. He has had one of the longest running NIH R01 grants at 39 years from the NCI for his research on the "Control of Enzymatic Phosphate Transfer in Mitochondria'.

Dr. Pedersen has been an invited lecturer on Cancer, Mitochondrial ATP Synthase, Transport ATPases, and Cystic Fibrosis at locations throughout the world. He has presented symposia papers on ATP synthesis and ATP hydrolysis in Lucerne, Switzerland; Hamburg, Germany; and Jerusalem, Israel. He is an honored member of several professional and honorary societies, and has served on several editorial boards and outside committees. Dr. Pedersen has been an active member of several study sections during his tenure.

Lastly, Dr. Pedersen has been a prolific author, having published over 366 articles with abstracts and 241 without abstracts. These publications serve as an indelible reminder of his numerous research accomplishments, as listed below.

RESEARCH ACCOMPLISHMENTS (With Co-Workers and Collaborators)

A. Participated with Drs. Carl Schnaitman, Jack W. Greenawalt, and T.L. Chan in the development of procedures routinely used today for the separation of the 4 components of mitochondria (inner membrane, outer membrane, inter-membrane space, and matrix) (Publications 8, 10, and 12). [This procedure and modified versions thereof have been used to determine the submitochondrial location of almost every known mitochondrial enzyme.]

B. Characterized mitochondrial nucleoside diphosphokinase with regard to enzymatic and hydrodynamic properties, submitochondrial location, and function (Publications 5, 6, 7, 8, 9, 10, and 22). [Mutations in this enzyme are now known to cause developmental problems in Drosophila. This enzyme is also believed to be involved in the development of certain childhood tumors, e.g., neuroblastomas, and to be involved also in cancer metastasis.]

C. Helped guide work of a number of predoctoral students and postdoctoral fellows that led to the purification from liver mitochondria of the c omplete ATP synthase complex and its associated F1-ATPase, F0 proton channel, and inhibitory peptide regulator (Publications 15, 17, 21, 39, 45, 62, and 92). [The ATP synthase complex, present in all nucleated cells, provides ATP either directly to energize cellular processes or indirectly as NTPs through the action of the above nucleoside diphosphokinase.]

D. Guided work of William Catterall that demonstrated concurrently with Drs. Alan Senior and Alex Tzagoloff (then at the U. of Wisconsin) that the catalytic F1 moiety of ATP synthases is comprised of 5 non-identical subunits (Publications 15 and 21). We were the first to observe both α and β subunits of F1 in SDS-PAGE gels (Publication 17), and to demonstrate the unusual α3β3γδε stoichiometry (Publications 15) and 21). These finding have now been reproduced for all ATP synthases from bacteria to people. Finally, we were also able to demonstrate with an electron microscopist (Glenn Decker) that the F1 moiety consists of a hexagonal array of subunits (α and β) with a central mass, predicted to be the small subunits (γδε). (Publication 3 under “Review articles” etc. ((this link goes to CV pdf from site)). [The F1 moiety of the ATP synthase is now known from work of Yoshida and coworkers in Japan to be an ATP hydrolysis driven motor and the small central subunits (γδε) the rotor of this motor. In mitochondria the enzyme works in reverse being driven by an electrochemical gradient of protons to make ATP as proposed by Peter Mitchell’s chemiosmotic hypothesis.]

E. Obtained crystals of the catalytic F1 moiety of the ATP synthase for the first time (1978) together with Mario Amzel, now Chair of Biophysics, JHUSOM, (Publications 34) and 37), and then collaborated with Mario Amzel, Michael McKinney, and P. Narayanan to elucidate the 3-dimensional structure of the enzyme complex at 9 Å resolution (Publication 58). Finally, in a collaborative project with Mario Bianchet and Mario Amzel, the structure of F1 was obtained first at 3.6 Å resolution (Publication 105) and finally at atomic resolution (2.8 Å) (Publication 135). The final structure represents the first of the active conformation. Most recently, a transition state structure (Publication 157) in the presence of vanadate has been obtained with crystals prepared by Dr. Young Ko via a project led by her in collaboration with the NIH laboratory headed by David Garboczi. [The importance of the latter work (157) is that it shows for the first time how ATP is made at the active site of the complex ATP synthase.]

F. First to visualize with colleagues John Soper, Glenn Decker, Jack Greenawalt, Maureen McEnery, M., Buhle, Jr., and U. Aebi, the structure of a complete ATP synthase molecule under the electron microscope (Publications 45), and 62). This has now led to the discovery by Young Ko that the ATP synthase in mitochondria exists as a larger complex consisting also of the adenine nucleotide carrier and the phosphate carrier.[The complete ATP synthase/phosphate carrier/adenine nucleotide carrier complex isolated in pure form by Young Ko has been named the “ATP synthasome” ] (Publications 150). A 3-D structure of this large super complex has been obtained at 23 Å resolution by Young Ko and Chen Chen in collaboration with the laboratory of Wah Chiu at Baylor College of Medicine (Publication 153).

G. Prepared morphologically and functionally intact mitochondria from hepatoma tissue (Publication 13). [This was the first clear demonstration that tumor mitochondria have a normal capacity to make ATP.]

H. Helped guide work of Ernesto Bustamante (Publications 31) and 49) that showed that hexokinase bound to mitochondria of cancer cells is essential for the “Warburg Effect”, i.e., a high glycolytic activity even in the presence of oxygen. [Hexokinase binding to mitochondria now forms the clinical basis of PET analysis for detecting many cancers.] Guided work of Richard Nakashima in collaboration with Marco Colombini that showed that the outer mitochondrial membrane receptor for hexokinase (Publications 77) is a protein called VDAC. [It is now known from the work of others that hexokinase bound to VDAC helps immortalize cancer cells by preventing cell death by apoptosis]. Later, together with Richard Nakashima and Marco Paggi, the hexokinase bound to tumor mitochondria was purified and categorized as hexokinase 2 (HK-2) (Publication 86).

I. Help guide work of Krishan Arora that demonstrated that the bound hexokinase has preferred access to ATP generated by the mitochondria (Publication 88). A full length cDNA of the tumor enzyme was cloned, sequenced, and overexpressed in active form in E. coli (Publication (99), and the first site directed mutations marking the catalytic site were completed (Publication 104). Krishan Arora showed also that tumor hexokinase is a protein kinase (Publication 114). Significantly, the predominant form of tumor hexokinase has been confirmed in work by Annette Rempel and Saroj Mathupala as HK-2. The HK-2 promoter region has now been isolated and sequenced (Publication 121). Finally, the HK-2 gene has been shown to be amplified (Publication 126) and to be activated by the mutated tumor suppressor p53 (Publication 131) as well as glucose, hypoxic conditions, and a variety of known transcription factors (Publications 144), 151, 152). In other work Ashish Goel presented evidence that the proximal promoter region of the HK-2 gene has several methylation sites that are demethylated in a highly malignant hepatoma cell line (Publication 151) and Min Gyu Lee has demonstrated that much of the strength of the the HK-2 promoter region lies near the transcription start site (Publication 152).

J. Helped guide experiments of Young Ko and collaborators where she independently discovered that the simple alkylating agent 3-bromopyruvate (3BP) is a powerful anticancer agent in cells in culture. This agent was shown also to be a powerful inhibitor of cancers in animal models (Publications 142, 146, 155). A single injection of 3BP into liver implanted tumors kills 70-90 percent of the tumor cells (Publication 146), and systemic injection suppresses metastatic lung cancers (Publication 146). Significantly, in a project led by Young Ko, advanced hepatocellular carcinomas growing in a rodent model were eradicated in all tested cases without apparent toxicity and without recurrence (Publication 155). More recent work by Young Ko has demonstrated that 3-bromopyruvate is far superior in killing human cancer cells in culture (derived from a wide variety of tissues) than a number of different chemotherapeutic agents widely used to treat human cancers.

K. Helped guide experiments of William Coty to label the mitochondrial phosphate transport system, and estimate its molecular size (Publication 25); later via the involvement of several Postdoctoral Fellows (Ronald Kaplan, Gloria Ferreria, and Raymond Pratt) this transport system was purified, cloned and sequenced, and its import into mitochondria clearly demonstrated (Publications 60, 78, 95, and 102).

L. Helped guide work of Ronald Kaplan that resulted in the first method for obtaining a reconstitutively active dicarboxylate carrier from mitochondria (Publication 74).

M. Helped guide work of William Coty and Janna Wehrle that showed that calcium is transported from the mitochondrial matrix to the cytoplasm (Publications 19 and 47). Later exit mechanisms for Ca++ from mitochondria became widely identified in many tissues.

N. Helped guide work of Naomi Geller that showed that the inner and outer mitochondrial membranes are subject to different rates of degradation and synthesis in vivo. This work led us to propose the first in vivo model for mitochondrial biogenesis (Publications 50 and 55).

O. Helped design and have synthesized with David Garboczi a peptide predicted from homology arguments to be at the catalytic site of the mitochondrial ATP synthase, and then demonstrated that this peptide does, in fact, interact with ATP (See Publication 84) [First, chemical synthesis of an ATP binding site]. The NMR structure of this peptide in the presence of ATP was later elucidated in a collaborative study with Albert Mildvan and W-J Chuang (Publication 122).

P. Helped guide work of David Gaboczi that resulted in the overproduction of both α and β subunits of rat liver ATP synthase in E. coli, purified them to homogeneity, and showed they bind nucleotide (Publications 87 and 98). Site directed, random, and deletion mutations were made to localize the nucleotide binding domain of the β “catalytic” subunits (Publications 100 and 109).

Q. Helped guide work of John Barnard that led to the characterization of the terminal steps of glycolysis in African trypanosomes that cause African sleeping sickness (Publications 89, 111, and 118). Significantly, a single enzyme (pyruvate kinase) supplies all the ATP to energize trypanosomal division and replication in the infectious form of this parasite and is therefore a potential drug target.

R. Helped guide work of Philip Thomas to design and have P, Shenbagamurthi, synthesize a 67 amino acid peptide corresponding to the central region of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), and showed it binds ATP. Postulated with these collaborators and others a simple structural model to explain the chemical basis of Cystic Fibrosis (Publication 103). Helped guide additional work of Philip Thomas to have P. Shenbagamurthi synthesize the CFTR peptide lacking the phenyalanine (F508), the deletion responsible for 70% of CF cases, and demonstrated it is structurally different from the wild type peptide (Publication 107). These studies were the first to obtain "in the test tube" a functional part of the CFTR protein and to implicate that most cases of the disease Cystic Fibrosis are the result of a protein folding problem (Publication 110). Later, helped guide work of Young Ko that demonstrated that the first nucleotide binding domain functions as a weak but active ATPase (Publication 123). Help guide work initiated by Young Ko that led Drs. Michael Massiah and Albert Mildvan to obtain by NMR the solution structures of folded and unfolded peptides representative of both the normal region and the diseased causing δF508 region of the CFTR protein (Publication 138) . This is the first work to show at a 3-dimensional level the structural change caused by the δF508 disease causing mutation that is responsible for most cases of Cystic Fibrosis.

S. First to predict with Philip Thomas and Young Ko that many common genetic diseases may result because of problems in protein folding (Publication 110 and Publication 56 under “Review Articles”).

T. Helped design with Young Ko and have chemically synthesized a 51 amino acid segment of the second predicted nucleotide binding domain of CFTR and showed that it also binds ATP (Publication 117).

U. Helped guide the original work of Young Ko who confirmed her hypothesis that tracheal epithelial cells in vitro have the capacity to kill bacteria (P. aeruginosa) that infect the lungs of most people, but not those of CF patients whose lungs have a defective CFTR protein. This work resulted in the discovery that human tracheal epithelial cells express one or more antimicrobial peptides (Publication 129) that protect most people against lung infections but not δF508 CF patients.

V. Designated together with Dr. Ernesto Carafoli the simple classification for Transport ATPases as P, V, and F types and later extended this to include the ABC-type Transport ATPases. This classification is now used in almost all publications on the subject (Publication 32) under “Review Articles etc.”). Also, see Publications 47, 69, and 71 under “Review Articles” etc.).