24-Thiacycloartanol, a potent mechanism-based inactivator of plant sterol methyltransferase

Zhou, Wenxu; Song, Zhihong; Liu, Jialin; Miller, Matthew B.; Nes, W. David

doi:10.1016/j.tetlet.2003.10.203

Cited by 13 publications

(13 citation statements)

References 15 publications

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“…Compound 41 was tested as an inhibitor of soybean SMT1 and found to be a noncompetitive inhibitor with a K i value of 55 nM and when added to the SMT assay it was not time-dependent [45]. These results suggest that 41 can inhibit SMT via ionic interactions according to path c (Scheme 5).…”

Section: Rational Design Of Potent Inhibitors Of Smtmentioning

confidence: 93%

“…The compounds shown in Scheme 4 have been tested and found to be noncompetitive inhibitors against the native substrate of the SMT [22,23,28,39]. In spite of numerous side chain modifications [38,[40][41][42][43][44][45][46][47], only a limited number of structural variants exhibit binding affinities to the enzyme active site that are significantly greater than those of the native substrate.…”

Section: Rational Design Of Potent Inhibitors Of Smtmentioning

confidence: 99%

“…In work with the yeast SMT, 25-azalanosterol was discovered to bind to the active center with a K d value of 4 µM similar to either the K d values of zymosterol or AdoMet at 4 µM [20]. The expectation for tight binding was borne out by the results of the 24-and 25-heteroatom substituted sterols assayed with SMT1 and SMT2, the carbocation mimic was bound to the Michaelis complex many orders more tightly than the sterol (or AdoMet) substrate generating a K m /K i ratio of approximately 1000 [16,23,38,[40][41][42][43][44][45][46]. The efficacy of 25-azacycloartenol, a substrate mimic, and solasodine have been compared in vitro and in vivo with the pathogenic yeastlike microbe P. wickerhamii which synthesizes ergosterol by the cycloartenol-cyclolaudenol route shown in Scheme 1.…”

Section: Rational Design Of Potent Inhibitors Of Smtmentioning

confidence: 99%

“…Two hypothetical mechanisms have been considered for the mode of action of 36 and 40 (Scheme 5). Compounds 36 and 40 have been tested with SMT1 from fungi and plants and protozoa [23,[44][45][46]. Compound 36 is a tight-binding reversible inhibitor K i of 10 nM lacking any time-dependent inhibition of activity thereby suggesting that it is a high energy intermediate.…”

Section: Rational Design Of Potent Inhibitors Of Smtmentioning

confidence: 99%

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Mechanism-based Enzyme Inactivators of Phytosterol Biosynthesis

et al. 2004

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Current progress on the mechanism and substrate recognition by sterol methyl transferase (SMT), the role of mechanism-based inactivators, other inhibitors of SMT action to probe catalysis and phytosterol synthesis is reported. SMT is a membrane-bound enzyme which catalyzes the coupled C-methylation-deprotonation reaction of sterol acceptor molecules generating the 24-alkyl sterol side chains of fungal ergosterol and plant sitosterol. This C-methylation step can be rate-limiting in the post-lanosterol (fungal) or post-cycloartenol (plant) pathways. A series of sterol analogs designed to impair SMT activity irreversibly have provided deep insight into the C-methylation reaction and topography of the SMT active site and as reviewed provide leads for the development of antifungal agents.

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Section: Rational Design Of Potent Inhibitors Of Smtmentioning

confidence: 93%

Section: Rational Design Of Potent Inhibitors Of Smtmentioning

confidence: 99%

Section: Rational Design Of Potent Inhibitors Of Smtmentioning

confidence: 99%

Section: Rational Design Of Potent Inhibitors Of Smtmentioning

confidence: 99%

See 2 more Smart Citations

Mechanism-based Enzyme Inactivators of Phytosterol Biosynthesis

et al. 2004

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“…The first studies directed at defining the structural parameters necessary for substrate recognition and subsequent initiation of the C-methylation reaction catalyzed by different SMT isoforms were confirmed and extended by examining the natures and magnitudes of inhibition (measured via experimentally determined K i /K m values) of a series of structurally related substrate analogs with nitrogen or sulfur introduced into the nucleus and/or side chain [35][36][37][38][39][40]. Using those nitrogen-containing analogs, which differ in a single structural feature but are otherwise similar to the natural substrate, and assuming that the recognition of an analog and natural substrate arises from a common set of enzyme interactions, it has been possible to identify and evaluate at least four critical structural elements of recognition involving the same four domains reported before for the sterol structure.…”

Section: Structurementioning

confidence: 99%

Sterol Biosynthesis Inhibitors: Potential for Transition State Analogs and Mechanism‐Based Inactivators Targeted at Sterol Methyltransferase

Song

Nes

2007

Lipids

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Sterol biosynthesis inhibitors (SBIs), discovered in the late 1960s and subsequently used commercially to treat ergosterol-dependent fungal diseases, represent a unique drug class targeted at an enzyme in a biosynthetic pathway. To date, few drugs have been commercialized as enzyme inhibitors; yet, prescription of SBIs has emerged as the gold standard for some cases of non-life-threatening antifungal chemotherapy and in crop protection. SBIs are not designed for their structural resemblance to the sterol molecule; they nonetheless can engender a curative effect by interfering with sterol production and homeostasis in the pathogenic organism. The increased use of SBIs in recent years, particularly the azole antifungals, has resulted in the development of resistance to those drugs, necessitating additional work to further our understanding of antifungal resistance and to explore opportunities to develop new enzyme inhibitors and uncover new enzyme targets that can regulate carbon flux in the post-lanosterol/cycloartenol pathway. This article reports general considerations for enzyme mechanism and active-site probes using inhibitors of the C-methylation reaction, including a potential new class of antifungal/antiparasitic agents of phytosterol synthesis tailored as mechanism-based inactivators. These steroid-based compounds prepared with different sterol side chain functionalities are designed to reversibly or irreversibly impair the sterol methyltransferase, an enzyme expressed in pathogenic microbes and plants but not in the human host. The salient aspects of these and related topics directed toward the enzyme recognition of sterol structure, and the inhibitory properties and catalytic competence of a series of specifically modified substrate analogs that affect sterol methyltransferase action are discussed.

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Structure and dynamics studies of sterol 24-C-methyltransferase with mechanism based inactivators for the disruption of ergosterol biosynthesis

et al. 2014

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The enzyme sterol 24-C-methyltransferase (SMT) belongs to the family of transferases, specifically to the one-carbon transferring methyltransferases. SMT has been found playing a major role during the production of steroids, especially for the biosynthesis of ergosterol, which is the major membrane sterol in leishmania parasites, causing leishmaniasis. However, SMT and ergosterol are not found in mammals, so, an extensive study has been carried out over the susceptible SMT protein, which is found to be highly conserved among all the Leishmania species and holds a significant anti-leishmanial drug target. To date, there is no computational data available for SMT, due to its highly unexplored profile. In this work, a complete set of structural attributes have been examined through the available computational procedures, along with an attempt to characterize the most capable modeling server available. The exploration ranges from physicochemical characterization, pairwise alignment, secondary structure prediction, to active site detection. With this information, a docking study was carried out to find the compound that best binds into the active site. Moreover, molecular dynamics simulation was conducted to examine the stability of the homology modeled protein and the ligand-enzyme complex. The results indicate that the ligand-enzyme complex is more stable.

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24-Thiacycloartanol, a potent mechanism-based inactivator of plant sterol methyltransferase

Cited by 13 publications

References 15 publications

Mechanism-based Enzyme Inactivators of Phytosterol Biosynthesis

Mechanism-based Enzyme Inactivators of Phytosterol Biosynthesis

Sterol Biosynthesis Inhibitors: Potential for Transition State Analogs and Mechanism‐Based Inactivators Targeted at Sterol Methyltransferase

Structure and dynamics studies of sterol 24-C-methyltransferase with mechanism based inactivators for the disruption of ergosterol biosynthesis

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