scholarly journals Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair

Science ◽  
2019 ◽  
Vol 366 (6465) ◽  
pp. 589-593 ◽  
Author(s):  
Markus Ruetz ◽  
Gregory C. Campanello ◽  
Meredith Purchal ◽  
Hongying Shen ◽  
Liam McDevitt ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Coenzyme A ◽  
Catalytic Cycle ◽  
Glyoxylate Shunt ◽  
Unknown Mechanism ◽  
Propionate Metabolism ◽  
Bactericidal Effects ◽  
Tertiary Carbon ◽  
Carbon Centered Radical ◽  
Inhibited Enzyme

Itaconate is an immunometabolite with both anti-inflammatory and bactericidal effects. Its coenzyme A (CoA) derivative, itaconyl-CoA, inhibits B12-dependent methylmalonyl-CoA mutase (MCM) by an unknown mechanism. We demonstrate that itaconyl-CoA is a suicide inactivator of human and Mycobacterium tuberculosis MCM, which forms a markedly air-stable biradical adduct with the 5′-deoxyadenosyl moiety of the B12 coenzyme. Termination of the catalytic cycle in this way impairs communication between MCM and its auxiliary repair proteins. Crystallography and spectroscopy of the inhibited enzyme are consistent with a metal-centered cobalt radical ~6 angstroms away from the tertiary carbon-centered radical and suggest a means of controlling radical trajectories during MCM catalysis. Mycobacterial MCM thus joins enzymes in the glyoxylate shunt and the methylcitrate cycle as targets of itaconate in pathogen propionate metabolism.

scholarly journals An essential role of acetyl coenzyme A in the catalytic cycle of insect arylalkylamine N-acetyltransferase

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Chu-Ya Wu ◽  
I-Chen Hu ◽  
Yi-Chen Yang ◽  
Wei-Cheng Ding ◽  
Chih-Hsuan Lai ◽  
...  
Keyword(s):  
Essential Role ◽  
Coenzyme A ◽  
Catalytic Cycle ◽  
Acetyl Coenzyme A ◽  
Acetyl Coenzyme

Coenzyme A metabolism

1985 ◽  
Vol 248 (1) ◽  
pp. E1-E9 ◽  
Author(s):  
J. D. Robishaw ◽  
J. R. Neely
Keyword(s):  
Enzyme Activity ◽  
Cardiac Muscle ◽  
Heart Muscle ◽  
Coenzyme A ◽  
Free Carnitine ◽  
Pantothenate Kinase ◽  
Acetyl Coenzyme A ◽  
Synthetic Pathway ◽  
And Control ◽  
Inhibited Enzyme

The metabolism of coenzyme A and control of its synthesis are reviewed. Pantothenate kinase is an important rate-controlling enzyme in the synthetic pathway of all tissues studied and appears to catalyze the flux-generating reaction of the pathway in cardiac muscle. This enzyme is strongly inhibited by coenzyme A and all of its acyl esters. The cytosolic concentrations of coenzyme A and acetyl coenzyme A in both liver and heart are high enough to totally inhibit pantothenate kinase under all conditions. Free carnitine, but not acetyl carnitine, deinhibits the coenzyme A-inhibited enzyme. Carnitine alone does not increase enzyme activity. Thus changes in the acetyl carnitine-to-carnitine ratio that occur with nutritional states provides a mechanism for regulation of coenzyme A synthetic rates. Changes in the rate of coenzyme A synthesis in liver and heart occurs with fasting, refeeding, and diabetes and in heart muscle with hypertrophy. The pathway and regulation of coenzyme A degradation are not understood.

Valproate in the Treatment of Seizures Associated with Propionic Acidemia

PEDIATRICS ◽  
1981 ◽  
Vol 67 (1) ◽  
pp. 162-163
Author(s):  
Barry Wolf ◽  
Elsa P. Paulsen ◽  
F. E. Dreifuss
Keyword(s):  
Coenzyme A ◽  
Propionic Acidemia ◽  
Propionate Metabolism ◽  
Metabolic Consequence ◽  
Convulsive Disorders ◽  
Nonketotic Hyperglycinemia

MacDermont et al1 (Pediatrics 65:624, 1980) have described the uncomplicated efficacy of valproate in treating the seizures of two patients with nonketotic hyperglycinemia even though valproate elevates urinary and serum glycine concentrations in individuals with convulsive disorders.2,3 Recent observations of increased urinary propionate excretion as a metabolic consequence of valproate therapy in two patients with seizures seem to contraindicate its use in children with disorders of propionate metabolism.4 However, we have successfully and safely used valproate to control seizures in a patient with propionyl coenzyme A carboxylase (PCC) deficiency, a disorder characterized by both hyperglycinemia and propionic acidemia.

scholarly journals Enhanced Bactericidal Effects of Pyrazinamide Toward Mycobacterium smegmatis and Mycobacterium tuberculosis upon Conjugation to a {Au(I)-triphenylphosphine}+ Moiety

ACS Omega ◽  
2020 ◽  
Vol 5 (12) ◽  
pp. 6826-6833 ◽  
Author(s):  
Jenny Stenger-Smith ◽  
Mireille Kamariza ◽  
Indranil Chakraborty ◽  
Ramatoulaye Ouattara ◽  
Carolyn R. Bertozzi ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Smegmatis ◽  
Bactericidal Effects

scholarly journals Biochemical and Structural Characterization of an Essential Acyl Coenzyme A Carboxylase from Mycobacterium tuberculosis

2006 ◽  
Vol 188 (2) ◽  
pp. 477-486 ◽  
Author(s):  
Gabriela Gago ◽  
Daniel Kurth ◽  
Lautaro Diacovich ◽  
Shiou-Chuan Tsai ◽  
Hugo Gramajo
Keyword(s):  
Fatty Acids ◽  
Mycobacterium Tuberculosis ◽  
Coenzyme A ◽  
Physiological Role ◽  
Kinetic Properties ◽  
Aliphatic Chain ◽  
Heterologous Protein Expression ◽  
Main Role ◽  
Enzyme Complex ◽  
Protein Expression And Purification

ABSTRACT Pathogenic mycobacteria contain a variety of unique fatty acids that have methyl branches at an even-numbered position at the carboxyl end and a long n-aliphatic chain. One such group of acids, called mycocerosic acids, is found uniquely in the cell wall of pathogenic mycobacteria, and their biosynthesis is essential for growth and pathogenesis. Therefore, the biosynthetic pathway of the unique precursor of such lipids, methylmalonyl coenzyme A (CoA), represents an attractive target for developing new antituberculous drugs. Heterologous protein expression and purification of the individual subunits allowed the successful reconstitution of an essential acyl-CoA carboxylase from Mycobacterium tuberculosis, whose main role appears to be the synthesis of methylmalonyl-CoA. The enzyme complex was reconstituted from the α biotinylated subunit AccA3, the carboxyltransferase β subunit AccD5, and the ε subunit AccE5 (Rv3281). The kinetic properties of this enzyme showed a clear substrate preference for propionyl-CoA compared with acetyl-CoA (specificity constant fivefold higher), indicating that the main physiological role of this enzyme complex is to generate methylmalonyl-CoA for the biosynthesis of branched-chain fatty acids. The α and β subunits are capable of forming a stable α6-β6 subcomplex but with very low specific activity. The addition of the ε subunit, which binds tightly to the α-β subcomplex, is essential for gaining maximal enzyme activity.

scholarly journals Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition

Science ◽  
2019 ◽  
Vol 363 (6426) ◽  
pp. eaau8959 ◽  
Author(s):  
Elaine Ballinger ◽  
John Mosior ◽  
Travis Hartman ◽  
Kristin Burns-Huang ◽  
Ben Gold ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Coenzyme A ◽  
Loss Of Function ◽  
Phosphopantetheinyl Transferase ◽  
Carrier Proteins ◽  
Regulatory Pathway ◽  
Acyl Carrier Proteins ◽  
Antimycobacterial Agents ◽  
Further Development ◽  
Cocrystal Structure

Mycobacterium tuberculosis (Mtb) is the leading infectious cause of death in humans. Synthesis of lipids critical for Mtb’s cell wall and virulence depends on phosphopantetheinyl transferase (PptT), an enzyme that transfers 4′-phosphopantetheine (Ppt) from coenzyme A (CoA) to diverse acyl carrier proteins. We identified a compound that kills Mtb by binding and partially inhibiting PptT. Killing of Mtb by the compound is potentiated by another enzyme encoded in the same operon, Ppt hydrolase (PptH), that undoes the PptT reaction. Thus, loss-of-function mutants of PptH displayed antimicrobial resistance. Our PptT-inhibitor cocrystal structure may aid further development of antimycobacterial agents against this long-sought target. The opposing reactions of PptT and PptH uncover a regulatory pathway in CoA physiology.

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