Inhibition of β-Ketoacyl-Acyl Carrier Protein Synthases by Thiolactomycin and Cerulenin

Price, Allen C.; Choi, Keum-Hwa; Heath, Richard J.; Li, Zhenmei; White, Stephen W.; Rock, Charles O.

doi:10.1074/jbc.m007101200

Cited by 324 publications

(425 citation statements)

References 55 publications

Supporting

Mentioning

380

Contrasting

Unclassified

Order By: Relevance

“…6 As for C75 and cerulenin, two other known FAS inhibitors, it has been reported that they inhibit FAS by irreversibly binding to the the ketoacyl synthase of FAS, and that their inhibition of FAS is related to the binding site of the substrate Mal-CoA or Ac-CoA. 6,17,18 Therefore, as regards inhibition mechanism, GE is totally different from the other three inhibitors previously reported. In addition, GE can possibly affect other sites of FAS besides the ketoacyl reductase, because the IC 50 values for the overall reaction and ketoacyl reductase are not identical.…”

Section: Discussionmentioning

confidence: 72%

Presence of Fatty Acid Synthase Inhibitors in the Rhizome ofAlpinia officinarumHance

Tian

2003

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

The galangal (the rhizome of Alpinia officinarum, Hance) is popular in Asia as a traditional herbal medicine. The present study reports that the galangal extract (GE) can potently inhibit fatty-acid synthase (FAS, E.C.2.3.1.85). The inhibition consists of both reversible inhibition with an IC 50 value of 1.73 mg dried GE/ml, and biphasic slow-binding inactivation. Subsequently the reversible inhibition and slow-binding inactivation to FAS were further studied. The inhibition of FAS by galangin, quercetin and kaempferol, which are the main flavonoids existing in the galangal, showed that quercetin and kaempferol had potent reversible inhibitory activity, but all three flavonoids had no obvious slow-binding inactivation. Analysis of the kinetic results led to the conclusion that the inhibitory mechanism of GE is totally different from that of some other previously reported inhibitors of FAS, such as cerulenin, EGCG (epigallocatechin gallate) and C75.

show abstract

Section: Discussionmentioning

confidence: 72%

Presence of Fatty Acid Synthase Inhibitors in the Rhizome ofAlpinia officinarumHance

Tian

2003

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…By using this assay, we measured the condensation activity of KasA in the presence of various drugs. Activated INH did not inhibit KasA activity in vitro, whereas CER, a known inhibitor of ␤-ketoacyl-ACP synthases (34,64), inhibited the activity very efficiently. In contrast, and as reported by others (65), KatG-activated INH strongly inhibited InhA activity.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of InhA Activity, but Not KasA Activity, Induces Formation of a KasA-containing Complex in Mycobacteria

Kremer

Dover

Morbidoni

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

(6) further demonstrated that the inhibition of mycolic acid biosynthesis mediated by INH leads to the accumulation of a saturated C 26 fatty acid within 1 h of INH treatment. By using scanning electron microscopy, it was established that M. tuberculosis treated with INH undergoes a defined order of molecular events that leads to lysis 24 h after initiation of treatment, thus after approximately one cell generation (7). The events that lead from the inhibition of mycolic acid biosynthesis and the accumulation of a saturated C 26 fatty acid to cell lysis are still poorly understood. Moreover, there exists controversy as to which enzymes of the mycolic acid biosynthetic pathway are the actual targets of INH.The mode of action of INH appears to be rather complex and requires activation by the mycobacterial catalase-peroxidase KatG (8,9). Activation of the pro-drug leads to reactive radicals that exert a toxic effect on the tubercle bacillus (9 -11). Presumably activated INH inhibits one or more targets of the mycolic acid biosynthetic pathway which eventually leads to cell death. At least two enzymes have been identified as potential targets of activated INH, the enoyl-ACP reductase InhA (12) and the ␤-ketoacyl-ACP synthase KasA (13). The inhA gene was first identified by conferring co-resistance to INH and ethionamide (ETH) after overexpression in mycobacteria (12). In addition, mutations in inhA confer resistance to both INH and ETH in drug-resistant M. tuberculosis isolates (14 -17).

show abstract

“…PctT is also highly homologous to ChlB3, ChlB6 [19], AviN [16], and CalO4 [17], all of which accompany with an iterative type I PKS. These homologous proteins were presumed to attach the starter unit, acetyl CoA, onto the corresponding PKSs, since FabH enzymes use an acyl-CoA rather than an acyl-ACP as the primer and catalyze the first condensation step in the pathway [55,56]. PctT is thus proposed to catalyze the priming reaction with acetyl CoA onto a discrete ACP PctK, which would be specifically recognized by an iterative type I PKS PctS for the formation of 6-MSA.…”

Section: Functional Analysis Of the Pctl Gene Encoding A Glycosyltranmentioning

confidence: 99%

Cloning of the Pactamycin Biosynthetic Gene Cluster and Characterization of a Crucial Glycosyltransferase Prior to a Unique Cyclopentane Ring Formation

et al. 2007

View full text Add to dashboard Cite

The biosynthetic gene (pct) cluster for an antitumor antibiotic pactamycin was identified by use of a gene for putative radical S-adenosylmethionine methyltransferase as a probe. The pct gene cluster is localized to a 34 kb contiguous DNA from Streptomyces pactum NBRC 13433 and contains 24 open reading frames. Based on the bioinformatic analysis, a plausible biosynthetic pathway for pactamycin comprising of a unique cyclopentane ring, 3-aminoacetophenone, and 6-methylsalicylate was proposed. The pctL gene encoding a glycosyltransferase was speculated to be involved in an N-glycoside formation between 3-aminoacetophenone and UDP-N-acetyl-a -D-glucosamine prior to a unique cyclopentane ring formation. The pctL gene was then heterologously expressed in Escherichia coli and the enzymatic activity of the recombinant PctL protein was investigated. Consequently, the PctL protein was found to catalyze the expected reaction forming b-N-glycoside. The enzymatic activity of the PctL protein clearly confirmed that the present identified gene cluster is for the biosynthesis of pactamycin. Also, a glycosylation prior to cyclopentane ring formation was proposed to be a general strategy in the biosynthesis of the structurally related cyclopentane containing compounds.

show abstract

Inhibition of β-Ketoacyl-Acyl Carrier Protein Synthases by Thiolactomycin and Cerulenin

Cited by 324 publications

References 55 publications

Presence of Fatty Acid Synthase Inhibitors in the Rhizome ofAlpinia officinarumHance

Presence of Fatty Acid Synthase Inhibitors in the Rhizome ofAlpinia officinarumHance

Inhibition of InhA Activity, but Not KasA Activity, Induces Formation of a KasA-containing Complex in Mycobacteria

Cloning of the Pactamycin Biosynthetic Gene Cluster and Characterization of a Crucial Glycosyltransferase Prior to a Unique Cyclopentane Ring Formation

Contact Info

Product

Resources

About