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We study the cytochrome P450 monooxygenases of Bacillus megaterium, the genes that encode them and the analogous genes of rat liver. We address three basic questions. 1.) How is the expression of these P450 cytochromes regulated, especially by barbiturates? 2.) How do the structures of the B. megaterium P450s relate to their catalytic activities? 3.) How do the induction mechanisms of the bacterial P450 genes compare with those of the analogous barbiturate-inducible P450 genes of the rat? Specifically, we study the transcriptional regulation of the genes encoding a catalytically self-sufficient 119 kDa fatty acid monooxygenase (P450BM-3) and two smaller P450s (BM-1 & BM-2) all from B. megaterium and the genes encoding CYP2B1/2 of the rat. We?ve cloned and sequenced the B. megaterium genes, including the regulatory regions, and are determining how their expression is regulated by endogenous factors and by barbiturates. We?ve identified, cloned, characterized and established the function of a number of barbiturate-regulated DNA-binding proteins from both B. megaterium and the rat that are involved in the induction of the P450 cytochromes. Many of these proteins regulate transcription of the P450s by binding to a common nucleotide sequence ("Barbie box") that we?ve shown to be present in the 5?-flanking regions of essentially all barbiturate-inducible genes. These findings support our concept that the barbiturate-mediated induction processes in organisms ranging from bacteria to mammals are mechanistically related. We've also carried out site-specific mutagenesis studies on the P450BM-3 structural gene to elucidate the elements involved in the function of this unique protein. We've identified the critical amino acid residues involved in the binding of FMN to the apoprotein and those involved in substrate binding. We've also elucidated the pathway for electron flow through cytochrome P450BM-3 by studying the interaction of cytochrome c and its heme domain with the P450BM-3 reductase domain.
We study the cytochrome P450 monooxygenases of Bacillus megaterium, the genes that encode them and the analogous genes of rat liver. We address three basic questions. 1.) How is the expression of these P450 cytochromes regulated, especially by barbiturates? 2.) How do the structures of the B. megaterium P450s relate to their catalytic activities? 3.) How do the induction mechanisms of the bacterial P450 genes compare with those of the analogous barbiturate-inducible P450 genes of the rat? Specifically, we study the transcriptional regulation of the genes encoding a catalytically self-sufficient 119 kDa fatty acid monooxygenase (P450BM-3) and two smaller P450s (BM-1 & BM-2) all from B. megaterium and the genes encoding CYP2B1/2 of the rat. We?ve cloned and sequenced the B. megaterium genes, including the regulatory regions, and are determining how their expression is regulated by endogenous factors and by barbiturates. We?ve identified, cloned, characterized and established the function of a number of barbiturate-regulated DNA-binding proteins from both B. megaterium and the rat that are involved in the induction of the P450 cytochromes. Many of these proteins regulate transcription of the P450s by binding to a common nucleotide sequence ("Barbie box") that we?ve shown to be present in the 5?-flanking regions of essentially all barbiturate-inducible genes. These findings support our concept that the barbiturate-mediated induction processes in organisms ranging from bacteria to mammals are mechanistically related. We've also carried out site-specific mutagenesis studies on the P450BM-3 structural gene to elucidate the elements involved in the function of this unique protein. We've identified the critical amino acid residues involved in the binding of FMN to the apoprotein and those involved in substrate binding. We've also elucidated the pathway for electron flow through cytochrome P450BM-3 by studying the interaction of cytochrome c and its heme domain with the P450BM-3 reductase domain.
Armand J. Fulco is a biochemist/molecular biologist who has been a faculty member in the Department of Biological Chemistry, UCLA School of Medicine since 1965. After serving in the U.S. Army (1952-54) during the Korean war, he received a B.S. degree in Chemistry (1957) and a Ph.D. in Physiological Chemistry (1960), both from UCLA. He was an NIH postdoctoral trainee (1960-61 in the Lipid Laboratories at UCLA with Prof. James F. Mead and a NIH Fellow (1961-63) at Harvard University with Prof. Konrad Bloch. He returned to UCLA in 1963 as a research biochemist in the Dept. of Biophysics and Nuclear Medicine and became an assistant professor in the Dept. of Biological Chemistry, UCLA School of Medicine in 1965 and a full professor in 1976. Since Oct. 2003 he has been professor emeritus (recalled to service) in the Dept. of Biological Chemistry, UCLA School of Medicine. He has also been an elected member of the School of Medicine Faculty Executive Committee since 1995, a member of the Medical School Admissions Committee since 1989, a Sub-Committee Chair and member of the Executive Committee of Medical School Admissions since 1994. He has also been a member of the Medical School Admissions Policy Committee since 1995, has represented the School of Medicine on the Selection Committee of the Residency Program in Oral and Maxillofacial Surgery since 1996, served as Co-Director of the Lipid-Hormone Core Laboratory, UCLA Clinical Nutrition Unit from 1989-1996 and has served as a member of the National Institutes of Health Physiological Chemistry and Physical Biochemistry Study Sections. In addition, Dr. Fulco has served on the organizing committees of numerous international meetings and as an International board member for 7 international scientific conferences in lipid and P450 Biochemistry and as the organizer & chair of two of these meetings. He is also a member of the UCLA Molecular Biology Institute, the UCLA-Jonsson Comprehensive Cancer Center and the UCLA Center for the Study of Evolution and the Origin of Life. Armand Fulco's Honors/Recognition include Biography listing in Marquis Who's Who in America and in WhoÂs Who in the World, Distinguished Foreign Scientist Research Award from the National Institutes of Agrobiological Resources (Japan), Oct. 1999, Faculty/Staff Partnership Award, 1999-2000, presented by the UCLA STAFF ASSEMBLY, June 9, 2000 and the Excellence in Teaching Award, presented by the UCLA School of Medicine Class of 2006, April, 2004
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