scholarly journals Complete Reconstitution of the Human Coenzyme A Biosynthetic Pathway via Comparative Genomics

2002 ◽  
Vol 277 (24) ◽  
pp. 21431-21439 ◽  
Author(s):  
Matthew Daugherty ◽  
Boris Polanuyer ◽  
Michael Farrell ◽  
Michael Scholle ◽  
Athanasios Lykidis ◽  
...  
Keyword(s):  
Comparative Genomics ◽  
Biosynthetic Pathway ◽  
Coenzyme A

Coenzyme A and its derivatives: renaissance of a textbook classic

2014 ◽  
Vol 42 (4) ◽  
pp. 1025-1032 ◽  
Author(s):  
Frederica L. Theodoulou ◽  
Ody C.M. Sibon ◽  
Suzanne Jackowski ◽  
Ivan Gout
Keyword(s):  
Translational Regulation ◽  
Biosynthetic Pathway ◽  
Coenzyme A ◽  
Cellular Metabolism ◽  
Biosynthetic Enzymes ◽  
Protein Acetylation ◽  
Heat Stable ◽  
Structural Differences ◽  
Challenges And Opportunities ◽  
Metabolic Reactions

In 1945, Fritz Lipmann discovered a heat-stable cofactor required for many enzyme-catalysed acetylation reactions. He later determined the structure for this acetylation coenzyme, or coenzyme A (CoA), an achievement for which he was awarded the Nobel Prize in 1953. CoA is now firmly embedded in the literature, and in students’ minds, as an acyl carrier in metabolic reactions. However, recent research has revealed diverse and important roles for CoA above and beyond intermediary metabolism. As well as participating in direct post-translational regulation of metabolic pathways by protein acetylation, CoA modulates the epigenome via acetylation of histones. The organization of CoA biosynthetic enzymes into multiprotein complexes with different partners also points to close linkages between the CoA pool and multiple signalling pathways. Dysregulation of CoA biosynthesis or CoA thioester homoeostasis is associated with various human pathologies and, although the biochemistry of CoA biosynthesis is highly conserved, there are significant sequence and structural differences between microbial and human biosynthetic enzymes. Therefore the CoA biosynthetic pathway is an attractive target for drug discovery. The purpose of the Coenzyme A and Its Derivatives in Cellular Metabolism and Disease Biochemical Society Focused Meeting was to bring together researchers from around the world to discuss the most recent advances on the influence of CoA, its biosynthetic enzymes and its thioesters in cellular metabolism and diseases and to discuss challenges and opportunities for the future.

scholarly journals Inhibitors of Pantothenate Kinase: Novel Antibiotics for Staphylococcal Infections

2003 ◽  
Vol 47 (6) ◽  
pp. 2051-2055 ◽  
Author(s):  
Anthony E. Choudhry ◽  
Tracy L. Mandichak ◽  
John P. Broskey ◽  
Richard W. Egolf ◽  
Cynthia Kinsland ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Staphylococcus Aureus ◽  
Biosynthetic Pathway ◽  
Coenzyme A ◽  
Low Molecular Weight ◽  
Pantothenate Kinase ◽  
Staphylococcal Infections ◽  
Low Molecular Weight Compounds ◽  
Novel Antibiotics

ABSTRACT Pantothenate kinase (CoaA) catalyzes the first step of the coenzyme A biosynthetic pathway. Here we report the identification of the Staphylococcus aureus coaA gene and characterization of the enzyme. We have also identified a series of low-molecular-weight compounds which are effective inhibitors of S. aureus CoaA.

scholarly journals The Final Player in the Coenzyme A Biosynthetic Pathway

Structure ◽  
2003 ◽  
Vol 11 (8) ◽  
pp. 899-900 ◽  
Author(s):  
Nicholas O'Toole ◽  
Miroslaw Cygler
Keyword(s):  
Biosynthetic Pathway ◽  
Coenzyme A

Alteration of the coenzyme A biosynthetic pathway in neurodegeneration with brain iron accumulation syndromes

2014 ◽  
Vol 42 (4) ◽  
pp. 1069-1074 ◽  
Author(s):  
Paola Venco ◽  
Sabrina Dusi ◽  
Lorella Valletta ◽  
Valeria Tiranti
Keyword(s):  
Biosynthetic Pathway ◽  
Coenzyme A ◽  
Iron Accumulation ◽  
Disease Genes ◽  
Common Denominator ◽  
Mitochondrial Enzyme ◽  
Brain Iron ◽  
Inborn Errors ◽  
Pantothenate Kinase ◽  
Gene Coding

NBIA (neurodegeneration with brain iron accumulation) comprises a heterogeneous group of neurodegenerative diseases having as a common denominator, iron overload in specific brain areas, mainly basal ganglia and globus pallidus. In the past decade a bunch of disease genes have been identified, but NBIA pathomechanisms are still not completely clear. PKAN (pantothenate kinase-associated neurodegeneration), an autosomal recessive disorder with progressive impairment of movement, vision and cognition, is the most common form of NBIA. It is caused by mutations in the PANK2 (pantothenate kinase 2) gene, coding for a mitochondrial enzyme that phosphorylates vitamin B5 in the first reaction of the CoA (coenzyme A) biosynthetic pathway. A distinct form of NBIA, denominated CoPAN (CoA synthase protein-associated neurodegeneration), is caused by mutations in the CoASY (CoA synthase) gene coding for a bifunctional mitochondrial enzyme, which catalyses the final steps of CoA biosynthesis. These two inborn errors of CoA metabolism further support the concept that dysfunctions in CoA synthesis may play a crucial role in the pathogenesis of NBIA.

scholarly journals Vitamin imposters: Hijacking the biosynthesis of coenzyme A for antimicrobial drug development

2015 ◽  
Vol 37 (1) ◽  
pp. 19-23
Author(s):  
Marianne de Villiers ◽  
Erick Strauss
Keyword(s):  
Biosynthetic Pathway ◽  
Antimicrobial Agents ◽  
Coenzyme A ◽  
Mechanisms Of Action ◽  
Clinical Use ◽  
Bacterial Strains ◽  
Dna And Rna ◽  
Drawing Board ◽  
To Come ◽  
Made In

Humankind's struggle to find cures for infectious diseases is as old as humanity itself. During the last century, we have probably made the greatest advance in our battle against these diseases: the discovery of antibiotics. Importantly, the first antimicrobial agents introduced for clinical use in 1937, the sulfonamide drugs, act by hijacking the disease-causing organism's biosynthetic pathway for making folic acid, a vitamin that is required in the synthesis of DNA and RNA. Since then, many other antibiotics with diverse mechanisms of action have been discovered, and, by the early 1960s, it seemed as if any infection could be treated successfully with a course of antibiotics. However, since the first introduction of these drugs, we have also started to suffer our greatest defeat: bacterial strains that show resistance against nearly every antibiotic were often isolated within a few years of their first clinical use. We have been forced back to the drawing board to come up with new antimicrobials, and this has led us to revisit the antimetabolite inhibition strategy used by the sulfonamide drugs. This article discusses the recent advances that have made in discovering compounds that interfere with the biosynthesis of the essential metabolic cofactor coenzyme A (CoA) from pantothenate (vitamin B5).

scholarly journals Identification of the Polyhydroxyalkanoate (PHA)-Specific Acetoacetyl Coenzyme A Reductase among Multiple FabG Paralogs in Haloarcula hispanica and Reconstruction of the PHA Biosynthetic Pathway in Haloferax volcanii

2009 ◽  
Vol 75 (19) ◽  
pp. 6168-6175 ◽  
Author(s):  
Jing Han ◽  
Qiuhe Lu ◽  
Ligang Zhou ◽  
Hailong Liu ◽  
Hua Xiang
Keyword(s):  
Biosynthetic Pathway ◽  
Coenzyme A ◽  
Reductase Activity ◽  
Halophilic Archaea ◽  
Haloferax Volcanii ◽  
Pha Synthase ◽  
Haloarcula Marismortui ◽  
Coa Reductase ◽  
Haloarcula Hispanica ◽  
Acetoacetyl Coa Reductase

ABSTRACT Genome-wide analysis has revealed abundant FabG (β-ketoacyl-ACP reductase) paralogs, with uncharacterized biological functions, in several halophilic archaea. In this study, we identified for the first time that the fabG1 gene, but not the other five fabG paralogs, encodes the polyhydroxyalkanoate (PHA)-specific acetoacetyl coenzyme A (acetoacetyl-CoA) reductase in Haloarcula hispanica. Although all of the paralogous fabG genes were actively transcribed, only disruption or knockout of fabG1 abolished PHA synthesis, and complementation of the ΔfabG1 mutant with the fabG1 gene restored both PHA synthesis capability and the NADPH-dependent acetoacetyl-CoA reductase activity. In addition, heterologous coexpression of the PHA synthase genes (phaEC) together with fabG1, but not its five paralogs, reconstructed the PHA biosynthetic pathway in Haloferax volcanii, a PHA-defective haloarchaeon. Taken together, our results indicate that FabG1 in H. hispanica, and possibly its counterpart in Haloarcula marismortui, has evolved the distinct function of supplying precursors for PHA biosynthesis, like PhaB in bacteria. Hence, we suggest the renaming of FabG1 in both genomes as PhaB, the PHA-specific acetoacetyl-CoA reductase of halophilic archaea.

scholarly journals Reduced Flux through the Purine Biosynthetic Pathway Results in an Increased Requirement for Coenzyme A in Thiamine Synthesis in Salmonella enterica Serovar Typhimurium

2000 ◽  
Vol 182 (1) ◽  
pp. 236-240 ◽  
Author(s):  
Michael Frodyma ◽  
Aileen Rubio ◽  
D. M. Downs
Keyword(s):  
Salmonella Enterica ◽  
Biosynthetic Pathway ◽  
Coenzyme A ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Thiamine Pyrophosphate ◽  
Nutritional Requirement ◽  
Prior Work ◽  
Serovar Typhimurium ◽  
Thiamine Biosynthesis

ABSTRACT Work presented here establishes a connection between cellular coenzyme A (CoA) levels and thiamine biosynthesis in Salmonella enterica serovar Typhimurium. Prior work showed thatpanE mutants (panE encodes ketopantoate reductase) had a conditional requirement for thiamine or pantothenate. Data presented herein show that the nutritional requirement ofpanE mutants for either thiamine or pantothenate is manifest only when flux through the purine biosynthetic pathway is reduced. Further, the data show that under the above conditions it is the lack of thiamine pyrophosphate, and not decreased CoA levels, that directly prevents growth.

scholarly journals Uneven distribution of cobamide biosynthesis and dependence in bacteria predicted by comparative genomics

2018 ◽  
Author(s):  
Amanda N. Shelton ◽  
Erica C. Seth ◽  
Kenny C. Mok ◽  
Andrew W. Han ◽  
Samantha N. Jackson ◽  
...  
Keyword(s):  
Comparative Genomics ◽  
Biosynthetic Pathway ◽  
De Novo ◽  
Bacterial Species ◽  
Vitamin B ◽  
Biosynthetic Pathways ◽  
Biosynthesis Pathway ◽  
Data Set ◽  
Enzyme Families ◽  
Lower Ligand

AbstractThe vitamin B12 family of cofactors known as cobamides are essential for a variety of microbial metabolisms. We used comparative genomics of 11,000 bacterial species to analyze the extent and distribution of cobamide production and use across bacteria. We find that 86% of bacteria in this data set have at least one of 15 cobamide-dependent enzyme families, yet only 37% are predicted to synthesize cobamides de novo. The distribution of cobamide biosynthesis varies at the phylum level, with 57% of Actinobacteria, 45% of Proteobacteria, and 30% of Firmicutes, and less than 1% of Bacteroidetes containing the complete biosynthetic pathway. Cobamide structure could be predicted for 58% of cobamide-producing species, based on the presence of signature lower ligand biosynthesis and attachment genes. Our predictions also revealed that 17% of bacteria that have partial biosynthetic pathways, yet have the potential to salvage cobamide precursors. These include a newly defined, experimentally verified category of bacteria lacking the first step in the biosynthesis pathway. These predictions highlight the importance of cobamide and cobamide precursor crossfeeding as examples of nutritional dependencies in bacteria.

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