St. Jude Children's Research Hospital

About: St. Jude Children's Research Hospital is a healthcare organization based out in Memphis, Tennessee, United States. It is known for research contribution in the topics: Population & Virus. The organization has 9344 authors who have published 19233 publications receiving 1233399 citations. The organization is also known as: St. Jude Children's Hospital & St. Jude Hospital.

β-Ketoacyl-Acyl Carrier Protein Synthase III (FabH) Is a Determining Factor in Branched-Chain Fatty Acid Biosynthesis

Abstract: Bacteria synthesize fatty acids by using the type II, or dissociated, fatty acid synthase system. This biosynthetic pathway has been studied primarily in Escherichia coli, providing a fairly complete picture of the mechanisms that govern the synthesis of straight-chain saturated and unsaturated fatty acids (for reviews, see references 7, 24, and 25). The pathway consists of a collection of individual proteins encoded by unique genes that function in concert to produce the variety of fatty acid products found in bacteria. The genomes of a number of bacteria are now known, and all these organisms possess a highly related, and clearly identified, set of genes that carry out the reactions in the pathway. E. coli and many other gram-negative bacteria synthesize even-chain saturated and unsaturated fatty acids. Fatty acid synthesis is initiated by the condensation of acetyl-coenzyme A (acetyl-CoA) with malonyl-acyl carrier protein (malonyl-ACP) by β-ketoacyl-ACP synthase III, the product of the fabH gene (14, 15, 31). However, other bacteria produce such a great variety of fatty acid structures that E. coli cannot be considered typical (25). Many gram-positive organisms, such as the bacilli, staphylococci, and streptomycetes, produce odd- and even-carbon-number branched-chain fatty acids (20). These branched-chain fatty acid structures have either iso- or anteiso-methyl branches, and it is tenable to hypothesize that the FabH component in organisms like B. subtilis would be able to accept isovaleryl-CoA, isobutyryl-CoA, and 2-methylbutyryl-CoA as primers to produce these fatty acids. Thus, earlier work by Butterwork and Bloch (5), showing that acyl-CoA:ACP transacylase activity, one of the reactions catalyzed by FabH (31), in Bacillus cell extracts was selective for branched-chain acyl-CoAs is consistent with the idea that bFabH prefers these primers. Genetic experiments with B. subtilis demonstrate that these CoA thioesters are essential intermediates in fatty acid synthesis and arise from iso- and anteiso-branched α-keto acids derived from the biosynthetic pathways for the amino acids valine, leucine, and isoleucine (33, 34). The enzyme responsible for the formation of these acyl-CoAs is a specialized branched-chain α-keto acid dehydrogenase complex, and mutations in the activity of this enzyme system result in strains that are auxotrophic for branched-chain acids (34). The Streptomyces glaucescens FabH enzyme efficiently utilizes both butyryl-CoA and isobutyryl-CoA and is thought to be responsible for initiating branched-chain fatty acid synthesis in this organism (10). eFabH is selective for acetyl-CoA (12, 14, 15, 31), and its low activity with butyryl-CoA (12) suggests that bulkier branched-chain CoA thioesters may not be substrates, although this idea has not been experimentally tested. In addition to the FabH component, it is also possible that all of the enzymes of the elongation cycle in gram-negative organisms (FabF, FabG, FabZ, and FabI) cannot utilize branched-chain intermediates. The goal of this study was to biochemically characterize the FabH enzymes of B. subtilis and determine if the FabH component is unique among the enzymes of type II fatty acid synthases in its selectivity toward branched-chain intermediates.

Treatment of acute lymphoblastic leukemia : 30 years' experience at St. Jude Children's Research Hospital

Abstract: Background Therapy for childhood lymphoblastic leukemia has evolved during the past three decades, but key questions about what are the least toxic, most effective forms of treatment remain unanswered because of the lack of comprehensive follow-up information. Methods To assess long-term outcome in the series of clinical trials conducted at St. Jude Hospital, we compared the results of treatment typical of four eras: exploratory combination chemotherapy (era 1, 1962 to 1966; 91 patients), regimens for the control of meningeal leukemia (era 2, 1967 to 1979; 825 patients), limited intensification of therapy (era 3, 1979 to 1983; 428 patients), and extended intensification of therapy (era 4, 1984 to 1988; 358 patients). (“Intensification” refers to strategies of systemic chemotherapy that are more aggressive than conventional ones.) The major end points were survival and event-free survival; we also calculated the relative risk of treatment failure and the rate of relapse or death after treatment ended (post...

Repair of topoisomerase I-mediated DNA damage.

Abstract: Topoisomerase I (Top1) is an abundant and essential enzyme. Top1 is the selective target of camptothecins, which are effective anticancer agents. Top1-DNA cleavage complexes can also be trapped by various endogenous and exogenous DNA lesions including mismatches, abasic sites and carcinogenic adducts. Tyrosyl-DNA phosphodiesterase (Tdp1) is one of the repair enzymes for Top1-DNA covalent complexes. Tdp1 forms a multiprotein complex that includes poly(ADP) ribose polymerase (PARP). PARP-deficient cells are hypersensitive to camptothecins and functionally deficient for Tdp1. We will review recent developments in several pathways involved in the repair of Top1 cleavage complexes and the role of Chk1 and Chk2 checkpoint kinases in the cellular responses to Top1 inhibitors. The genes conferring camptothecin hypersensitivity are compiled for humans, budding yeast and fission yeast.