Isolation of the Lactobacillus bulgaricus Factor from Natural Sources<sup>1</sup>

Peters, Vincent J.; Brown, Gene M.; Williams, William L.; Snell, Esmond E.

doi:10.1021/ja01103a051

Cited by 8 publications

(2 citation statements)

References 6 publications

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“…Regardless of the mechanism or structural basis of the interaction between the growth inhibitory pantothenamides and SaPanK II , our finding that PantSH (the only pantothenamide known to occur naturally) [40,41] mirrors this complex and specific interaction suggests that it is a native ligand of the enzyme. Such a characteristic could be a compensatory regulatory mechanism for SaPanK II because, unlike other type I and type II PanKs, this enzyme does not experience any feedback inhibition by CoA or its thioesters [14].…”

Section: O M P E T I T I V E I N H I B I T I O N U N C O M P E T I mentioning

confidence: 90%

Variation in pantothenate kinase type determines the pantothenamide mode of action and impacts on coenzyme A salvage biosynthesis

et al. 2014

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N-substituted pantothenamides are analogues of pantothenic acid, the vitamin precursor of CoA, and constitute a class of well-studied bacterial growth inhibitors that show potential as new antibacterial agents. Previous studies have highlighted the importance of pantothenate kinase (PanK; EC 2.7.1.33) (the first enzyme of CoA biosynthesis) in mediating pantothenamide-induced growth inhibition by one of two proposed mechanisms: first, by acting on the pantothenamides as alternate substrates (allowing their conversion into CoA antimetabolites, with subsequent effects on CoA-and acyl carrier protein-dependent processes) or, second, by being directly inhibited by them (causing a reduction in CoA biosynthesis). In the present study we used structurally modified pantothenamides to probe whether PanKs interact with these compounds in the same manner. We show that the three distinct types of eubacterial PanKs that are known to exist (PanK I , PanK II and PanK III ) respond very differently and, consequently, are responsible for determining the pantothenamide mode of action in each case: although the promiscuous PanK I enzymes accept them as substrates, the highly selective PanK III s are resistant to their inhibitory effects. Most unexpectedly, Staphylococcus aureus PanK (the only known example of a bacterial PanK II ) experiences uncompetitive inhibition in a manner that is described for the first time. In addition, we show that pantetheine, a CoA degradation product that closely resembles the pantothenamides, causes the same effect. This suggests that, in S. aureus, pantothenamides may act by usurping a previously unknown role of pantetheine in the regulation of CoA biosynthesis, and validates its PanK as a target for the development of new antistaphylococcal agents.

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Section: O M P E T I T I V E I N H I B I T I O N U N C O M P E T I mentioning

confidence: 90%

Variation in pantothenate kinase type determines the pantothenamide mode of action and impacts on coenzyme A salvage biosynthesis

et al. 2014

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“…However, lactose alone was inactive in the absence of another unidentified factor, which we called the L. bulgaricus factor or LBF (46) . LBF occurred in several chromatograph ically different forms, one of which we purified about 3000-fold to near homogeneity (47). The key finding that LBF could be replaced by very large amounts of pantothenate (48) led us to suspect that LBF might be a combined form of this vitamin.…”

Section: Pantetheine-pantethinementioning

confidence: 97%

FROM BACTERIAL NUTRITION TO ENZYME STRUCTURE: A Personal Odyssey

Snell

1993

Annu. Rev. Biochem.

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As a former editor or member of the Editorial Board of the Annual Review of Biochemistry I helped to select authors of the prefatory chapters for more than 20 years. Now I am asked to write one myself. The first such chapter appeared in 1953 with the prefatorial statement: “This is the first of a series in which it is the hope of the Editorial Committee that our elders in biochemistry will give us through chapters of a historical and philosophical character the benefit of their long years of experience in biochemistry.” With one exception, the chapters have appeared regularly ever since. Their authors comprise a group I am proud to join even while harboring some doubts about really belonging. Their autobiographical accounts have added much to our understanding of how and why they became biochemists, and how biochemistry itself developed. I shall continue in this tradition.

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