The lipid A assembly pathway: the work of Christian Raetz

During his career, Christian Raetz has characterized many enzymes responsible for synthesizing or modifying lipid molecules, including the entire nine-enzyme pathway for the biosynthesis of lipid A, an essential part of bacterial outer membranes that plays a role in making many Gram-negative bacteria toxic. The findings from the two Journal of Biological Chemistry (JBC) Classic articles reprinted here were the start of Raetz'' elucidation of the enzymology, genetics, and structural biology of lipid A assembly.Fatty Acyl Derivatives of Glucosamine 1-Phosphate in Escherichia coli and Their Relation to Lipid A. Complete Structure of a Diacyl GlcN-1-P Found in a Phosphatidylglycerol-deficient Mutant (Takayama, K., Qureshi, N., Mascagni, P., Nashed, M. A., Anderson, L., and Raetz, C. R. H. (1983) J. Biol. Chem. 258, 7379–7385)The Biosynthesis of Gram-negative Endotoxin. Formation of Lipid A Precursors from UDP-GlcNAc in Extracts of Escherichia coli (Anderson, M. S., Bulawa, C. E., and Raetz, C. R. H. (1985) J. Biol. Chem. 260, 15536–15541)Christian Rudolf Hubert Raetz was born in 1946 in East Berlin. His parents were industrial chemists, and in the early 1950s the family moved to Ohio so his father could work for the Olin Mathieson Chemical Corporation. Being surrounded by chemists, Raetz naturally gravitated toward science and would do experiments with chemicals his father brought home from the lab. After receiving his bachelor''s degree in chemistry from Yale University in 1967, Raetz enrolled in a combined medical/doctoral program at Harvard Medical School. There, he worked with Eugene Kennedy, studying the enzymatic mechanism of phosphatidylserine synthesis in Escherichia coli and the role of liponucleotides in membrane biogenesis. Raetz graduated in 1973 and became a postdoctoral fellow at the National Institutes of Health, working with long-time Journal of Biological Chemistry (JBC) Editor-in-Chief Herbert Tabor at the National Institute of General Medical Sciences. (Tabor was featured in a previous JBC Classic (1).)Open in a separate windowChristian Raetz (left) and Eugene Kennedy at Kennedy''s 90th birthday symposium in 2009. Raetz is holding a biochemistry textbook written by Kennedy''s research advisor Albert Lehninger; thus the picture shows three generations of the Lehninger line of biochemists. Kennedy and Lehninger were featured in previous JBC Classics (3, 4).In 1976, Raetz joined the biochemistry department at the University of Wisconsin-Madison as an assistant professor and soon rose to the rank of full professor. At Madison, Raetz decided to combine genetics and lipid research, screening for mutants that formed defective cell membrane lipids in hopes of discovering the functions of structurally diverse lipid molecules.While studying Escherichia coli mutants with a defect in phosphatidylglycerophosphate synthetase (2), Raetz discovered a novel lipid building up in these mutants, the structure of which suggested that it might be a precursor to a membrane component known as lipid A. As reported in the first JBC Classic reprinted here, Raetz and his colleagues subjected the lipid to analysis by fast atom bombardment mass spectrometry and proton NMR spectroscopy and established its complete structure. The novel glucosamine-based lipid indeed turned out to be a key precursor of lipid A, and its discovery enabled Raetz to postulate testable hypotheses for lipid A biosynthesis. The discovery was also significant because lipid A anchors lipopolysaccharide (LPS) to the outer membrane of E. coli, and LPS, in turn, plays a role in making many Gram-negative bacteria, such as E. coli and Salmonella, toxic.The second JBC Classic reprinted here shows how the diacylated monosaccharide lipid A precursors are synthesized from known molecules by the fatty acylation of UDP-GlcNAc. From these results, Raetz postulated that the partitioning of UDP-GlcNAc between the lipid A pathway and peptidoglycan biosynthesis represents an important control point in the biogenesis of the Gram-negative envelope.Together, the findings from both JBC papers were the start of Raetz'' elucidation of the enzymology, genetics, and structural biology of lipid A assembly (see Fig. 1).Open in a separate windowFIGURE 1Raetz also discovered a large number of additional lipid A modification enzymes that are unique to certain subsets of Gram-negative bacteria but that can be reconstituted by heterologous expression in E. coli or Salmonella. Many of these enzymes are located on the periplasmic surface of the inner membrane or in the outer membrane, making them useful as reporters for lipid A trafficking. Some lipid A modification enzymes confer resistance to antimicrobial peptides, whereas others are important during pathogenesis.In 1987, Raetz left Madison to become executive director of biochemistry at Merck Research Laboratories and eventually became vice president of basic research, biochemistry, and microbiology at Merck. In addition to his own research, which was concerned with the identification and development of new antibiotics that target lipid A biosynthesis, Raetz supervised several ongoing lipid projects that included the final stages of simvastatin/Zocor (one of the first, and most successful, clinically and commercially, statin drugs produced by Merck) and finasteride/Proscar (used to treat benign prostatic hyperplasia and male pattern baldness).In 1993, Raetz returned to academia as chairman of biochemistry at the Duke University Medical Center and began focusing on the structural biology of the enzymes that make up the lipid A pathway. Today, Raetz remains at Duke where he is a George Barth Geller Professor of Biochemistry.In recognition of his contributions to science, Raetz has received many awards and honors including the 1979 Camille and Henry Dreyfus Teacher-Scholar Award, the 2002 American Society for Biochemistry and Molecular Biology Avanti Award in Lipids, the 2006 L. L. M. van Deenen Medal from the University of Utrecht, the 2006 Frederik B. Bang Award from the International Endotoxin and Innate Immunity Society, and election to the National Academy of Sciences in 2006.