scholarly journals Mosaic evolution of the phosphopantothenate biosynthesis pathway in bacteria and archaea

2020 ◽  
Author(s):  
Luc Thomès ◽  
Alain Lescure
Keyword(s):  
Metabolic Pathways ◽  
Biosynthetic Pathway ◽  
Coenzyme A ◽  
Symbiotic Bacteria ◽  
Dynamic Evolution ◽  
Biosynthesis Pathway ◽  
Protein Annotation ◽  
Picrophilus Torridus ◽  
Domains Of Life ◽  
Mosaic Evolution

Abstract Phosphopantothenate is a precursor to synthesis of Coenzyme A (CoA), a molecule essential to many metabolic pathways. Organisms of the archaeal phyla were shown to utilize a different phosphopantothenate biosynthetic pathway from the eukaryotic and bacterial one. In this study, we report that symbiotic bacteria from the group Candidatus poribacteria present enzymes of the archaeal pathway, namely pantoate kinase (PoK) and phosphopantothenate synthetase (PPS), mirroring what was demonstrated for Picrophilus torridus, an archaea partially utilizing the bacterial pathway. Our results support the ancient origin of the CoA pathway in the three domains of life, but also highlight its complex and dynamic evolution. Importantly, this study helps to improve protein annotation for this pathway in the Candidatus poribacteria group and other related organisms.

scholarly journals Identification of Dephospho-Coenzyme A (Dephospho-CoA) Kinase in Thermococcus kodakarensis and Elucidation of the Entire CoA Biosynthesis Pathway in Archaea

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Takahiro Shimosaka ◽  
Kira S. Makarova ◽  
Eugene V. Koonin ◽  
Haruyuki Atomi
Keyword(s):  
Metabolic Pathways ◽  
Coenzyme A ◽  
Protein A ◽  
Biosynthesis Pathway ◽  
Content Type ◽  
Hyperthermophilic Archaeon ◽  
Thermococcus Kodakarensis ◽  
Uncharacterized Gene ◽  
Wide Range ◽  
Insight Into

ABSTRACT Dephospho-coenzyme A (dephospho-CoA) kinase (DPCK) catalyzes the ATP-dependent phosphorylation of dephospho-CoA, the final step in coenzyme A (CoA) biosynthesis. DPCK has been identified and characterized in bacteria and eukaryotes but not in archaea. The hyperthermophilic archaeon Thermococcus kodakarensis encodes two homologs of bacterial DPCK and the DPCK domain of eukaryotic CoA synthase, TK1334 and TK2192. We purified the recombinant TK1334 and TK2192 proteins and found that they lacked DPCK activity. Bioinformatic analyses showed that, in several archaea, the uncharacterized gene from arCOG04076 protein is fused with the gene for phosphopantetheine adenylyltransferase (PPAT), which catalyzes the reaction upstream of the DPCK reaction in CoA biosynthesis. This observation suggested that members of arCOG04076, both fused to PPAT and standalone, could be the missing archaeal DPCKs. We purified the recombinant TK1697 protein, a standalone member of arCOG04076 from T. kodakarensis, and demonstrated its GTP-dependent DPCK activity. Disruption of the TK1697 resulted in CoA auxotrophy, indicating that TK1697 encodes a DPCK that contributes to CoA biosynthesis in T. kodakarensis. TK1697 homologs are widely distributed in archaea, suggesting that the arCOG04076 protein represents a novel family of DPCK that is not homologous to bacterial and eukaryotic DPCKs but is distantly related to bacterial and eukaryotic thiamine pyrophosphokinases. We also constructed and characterized gene disruption strains of TK0517 and TK2128, homologs of bifunctional phosphopantothenoylcysteine synthetase-phosphopantothenoylcysteine decarboxylase and PPAT, respectively. Both strains displayed CoA auxotrophy, indicating their contribution to CoA biosynthesis. Taken together with previous studies, the results experimentally validate the entire CoA biosynthesis pathway in T. kodakarensis. IMPORTANCE CoA is utilized in a wide range of metabolic pathways, and its biosynthesis is essential for all life. Pathways for CoA biosynthesis in bacteria and eukaryotes have been established. In archaea, however, the enzyme that catalyzes the final step in CoA biosynthesis, dephospho-CoA kinase (DPCK), had not been identified. In the present study, bioinformatic analyses identified a candidate for the DPCK in archaea, which was biochemically and genetically confirmed in the hyperthermophilic archaeon Thermococcus kodakarensis. Genetic analyses on genes presumed to encode bifunctional phosphopantothenoylcysteine synthetase-phosphopantothenoylcysteine decarboxylase and phosphopantetheine adenylyltransferase confirmed their involvement in CoA biosynthesis. Taken together with previous studies, the results reveal the entire pathway for CoA biosynthesis in a single archaeon and provide insight into the different mechanisms of CoA biosynthesis and their distribution in nature.

scholarly journals Exploring Drug Targets in Isoprenoid Biosynthetic Pathway forPlasmodium falciparum

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Tabish Qidwai ◽  
Farrukh Jamal ◽  
Mohd Y. Khan ◽  
Bechan Sharma
Keyword(s):  
Antimalarial Drug ◽  
Metabolic Pathways ◽  
Drug Target ◽  
Drug Targets ◽  
Malaria Parasite ◽  
Biosynthetic Pathway ◽  
Comprehensive Analysis ◽  
Isoprenoid Biosynthesis ◽  
Biosynthesis Pathway ◽  
Novel Targets

Emergence of rapid drug resistance to existing antimalarial drugs inPlasmodium falciparumhas created the need for prediction of novel targets as well as leads derived from original molecules with improved activity against a validated drug target. The malaria parasite has a plant plastid-like apicoplast. To overcome the problem of falciparum malaria, the metabolic pathways in parasite apicoplast have been used as antimalarial drug targets. Among several pathways in apicoplast, isoprenoid biosynthesis is one of the important pathways for parasite as its multiplication in human erythrocytes requires isoprenoids. Therefore targeting this pathway and exploring leads with improved activity is a highly attractive approach. This report has explored progress towards the study of proteins and inhibitors of isoprenoid biosynthesis pathway. For more comprehensive analysis, antimalarial drug-protein interaction has been covered.

scholarly journals Itaconate Alters Succinate and Coenzyme A Metabolism via Inhibition of Mitochondrial Complex II and Methylmalonyl-CoA Mutase

Metabolites ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 117
Author(s):  
Thekla Cordes ◽  
Christian M. Metallo
Keyword(s):  
Amino Acid ◽  
Metabolic Pathways ◽  
Mammalian Cells ◽  
Coenzyme A ◽  
Cultured Cells ◽  
Tca Cycle ◽  
Regulatory Function ◽  
Reversible Inhibitor ◽  
Complex Ii ◽  
Branched Chain

Itaconate is a small molecule metabolite that is endogenously produced by cis-aconitate decarboxylase-1 (ACOD1) in mammalian cells and influences numerous cellular processes. The metabolic consequences of itaconate in cells are diverse and contribute to its regulatory function. Here, we have applied isotope tracing and mass spectrometry approaches to explore how itaconate impacts various metabolic pathways in cultured cells. Itaconate is a competitive and reversible inhibitor of Complex II/succinate dehydrogenase (SDH) that alters tricarboxylic acid (TCA) cycle metabolism leading to succinate accumulation. Upon activation with coenzyme A (CoA), itaconyl-CoA inhibits adenosylcobalamin-mediated methylmalonyl-CoA (MUT) activity and, thus, indirectly impacts branched-chain amino acid (BCAA) metabolism and fatty acid diversity. Itaconate, therefore, alters the balance of CoA species in mitochondria through its impacts on TCA, amino acid, vitamin B12, and CoA metabolism. Our results highlight the diverse metabolic pathways regulated by itaconate and provide a roadmap to link these metabolites to potential downstream biological functions.

scholarly journals Identification of Biomolecules Involved in the Adaptation to the Environment of Cold-Loving Microorganisms and Metabolic Pathways for Their Production

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1155
Author(s):  
Eva Garcia-Lopez ◽  
Paula Alcazar ◽  
Cristina Cid
Keyword(s):  
Metabolic Pathways ◽  
Extracellular Polymeric Substances ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Analytical Techniques ◽  
Light Protection ◽  
Domains Of Life ◽  
Mechanisms Of Adaptation ◽  
Resistance To Stress ◽  
Function Discovery

Cold-loving microorganisms of all three domains of life have unique and special abilities that allow them to live in harsh environments. They have acquired structural and molecular mechanisms of adaptation to the cold that include the production of anti-freeze proteins, carbohydrate-based extracellular polymeric substances and lipids which serve as cryo- and osmoprotectants by maintaining the fluidity of their membranes. They also produce a wide diversity of pigmented molecules to obtain energy, carry out photosynthesis, increase their resistance to stress and provide them with ultraviolet light protection. Recently developed analytical techniques have been applied as high-throughoutput technologies for function discovery and for reconstructing functional networks in psychrophiles. Among them, omics deserve special mention, such as genomics, transcriptomics, proteomics, glycomics, lipidomics and metabolomics. These techniques have allowed the identification of microorganisms and the study of their biogeochemical activities. They have also made it possible to infer their metabolic capacities and identify the biomolecules that are parts of their structures or that they secrete into the environment, which can be useful in various fields of biotechnology. This Review summarizes current knowledge on psychrophiles as sources of biomolecules and the metabolic pathways for their production. New strategies and next-generation approaches are needed to increase the chances of discovering new biomolecules.

scholarly journals Genetic Characterization of the Carotenoid Biosynthetic Pathway in Methylobacterium extorquens AM1 and Isolation of a Colorless Mutant

2003 ◽  
Vol 69 (12) ◽  
pp. 7563-7566 ◽  
Author(s):  
Stephen J. Van Dien ◽  
Christopher J. Marx ◽  
Brooke N. O'Brien ◽  
Mary E. Lidstrom
Keyword(s):  
Biosynthetic Pathway ◽  
Genetic Characterization ◽  
Carotenoid Biosynthesis ◽  
Biosynthesis Pathway ◽  
Wild Type ◽  
Methylobacterium Extorquens ◽  
Growth Properties ◽  
Carotenoid Biosynthesis Pathway ◽  
Free Strain

ABSTRACT Genomic searches were used to reconstruct the putative carotenoid biosynthesis pathway in the pink-pigmented facultative methylotroph Methylobacterium extorquens AM1. Four genes for putative phytoene desaturases were identified. A colorless mutant was obtained by transposon mutagenesis, and the insertion was shown to be in one of the putative phytoene desaturase genes. Mutations in the other three did not affect color. The tetracycline marker was removed from the original transposon mutant, resulting in a pigment-free strain with wild-type growth properties useful as a tool for future experiments.

scholarly journals Bornyl Diphosphate Synthase From Cinnamomum burmanni and Its Application for (+)-Borneol Biosynthesis in Yeast

2021 ◽  
Vol 9 ◽  
Author(s):  
Rui Ma ◽  
Ping Su ◽  
Juan Guo ◽  
Baolong Jin ◽  
Qing Ma ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Biosynthetic Pathway ◽  
Main Product ◽  
Microbial Fermentation ◽  
Biosynthesis Pathway ◽  
Analgesic Effects ◽  
Pathway Reconstruction ◽  
Key Enzyme ◽  
Shake Flasks

(+)-Borneol is a desirable monoterpenoid with effective anti-inflammatory and analgesic effects that is known as soft gold. (+)-bornyl diphosphate synthase is the key enzyme in the (+)-borneol biosynthesis pathway. Despite several reported (+)-bornyl diphosphate synthase genes, relatively low (+)-borneol production hinders the attempts to synthesize it using microbial fermentation. Here, we identified the highly specific (+)-bornyl diphosphate synthase CbTPS1 from Cinnamomum burmanni. An in vitro assay showed that (+)-borneol was the main product of CbTPS1 (88.70% of the total products), and the Km value was 5.11 ± 1.70 μM with a kcat value of 0.01 s–1. Further, we reconstituted the (+)-borneol biosynthetic pathway in Saccharomyces cerevisiae. After tailored truncation and adding Kozak sequences, the (+)-borneol yield was improved by 96.33-fold to 2.89 mg⋅L–1 compared with the initial strain in shake flasks. This work is the first reported attempt to produce (+)-borneol by microbial fermentation. It lays a foundation for further pathway reconstruction and metabolic engineering production of this valuable natural monoterpenoid.

CoA biosynthesis in archaea

2013 ◽  
Vol 41 (1) ◽  
pp. 427-431 ◽  
Author(s):  
Haruyuki Atomi ◽  
Hiroya Tomita ◽  
Takuya Ishibashi ◽  
Yuusuke Yokooji ◽  
Tadayuki Imanaka
Keyword(s):  
Metabolic Pathways ◽  
Current Status ◽  
Domains Of Life ◽  
Near Future

CoA is a ubiquitous molecule in all three domains of life and is involved in various metabolic pathways. The enzymes and reactions involved in CoA biosynthesis in eukaryotes and bacteria have been identified. By contrast, the proteins/genes involved in CoA biosynthesis in archaea have not been fully clarified, and much has to be learned before we obtain a general understanding of how this molecule is synthesized. In the present paper, we review the current status of the research on CoA biosynthesis in the archaea, and discuss important questions that should be addressed in the near future.

Dependence of heme biosynthesis on iron-sulfur cluster biogenesis: human ALAD is an unrecognized iron-sulfur protein

2020 ◽  
Author(s):  
Gang Liu ◽  
Debangsu Sil ◽  
Wing-Hang Tong ◽  
Nunziata Maio ◽  
J. Martin Bollinger ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Biosynthetic Pathway ◽  
Aminolevulinic Acid ◽  
Heme Biosynthesis ◽  
Second Step ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Sulfur Protein ◽  
Iron Sulfur Protein

Abstract Heme biosynthesis and iron-sulfur cluster (ISC) biogenesis are two major mammalian metabolic pathways that require iron. It has long been known that these two pathways interconnect, but the previously described interactions do not fully explain why heme biosynthesis depends on intact ISC biogenesis. Herein we have identified a previously unrecognized connection between these two pathways through our discovery that human aminolevulinic acid dehydratase (ALAD), which catalyzes the second step of heme biosynthesis, is an Fe-S protein. We found that several highly conserved cysteines and an Ala306-Phe307-Arg308 motif of human ALAD are important for [Fe4S4] cluster acquisition and coordination. The enzymatic activity of human ALAD was greatly reduced upon loss of its Fe-S cluster, which resulted in reduced heme biosynthesis in human cells. Our findings explain why heme biosynthesis depends on intact ISC biogenesis, as ALAD provides an early Fe-S-dependent checkpoint in the heme biosynthetic pathway.

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.

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