Sterol biosynthesis <i>de nova</i> via cycloartenol by the soil amoeba <i>Acanthamoeba polyphaga</i>

Raederstorff, Daniel; Rohmer, Michel

doi:10.1042/bj2310609

Cited by 51 publications

(60 citation statements)

References 51 publications

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“…The relatively low sequence identity (31 to 35%) of AcCYP51 with fungal CYP51 enzymes suggests that existing clinical azole antifungal drugs are not so efficacious against Acanthamoeba infections. The higher AcCYP51 reaction rate observed with obtusifoliol is in keeping with obtusifoliol being the most abundant in vivo CYP51 substrate in Acanthamoeba polyphaga (40), although substrate specificity was not absolute, as has been observed in Trypanosoma brucei CYP51 (41) and plant CYP51 enzymes (42,43). The substrate specificity of AcCYP51 was broader than that observed with Trypanosoma cruzi CYP51 (44) and Leishmania infantum CYP51 (45).…”

Section: Discussionmentioning

confidence: 58%

Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14α-Demethylase (CYP51)

Lamb

Warrilow

Rolley

et al. 2015

Antimicrob Agents Chemother

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In this study, we investigate the amebicidal activities of the pharmaceutical triazole CYP51 inhibitors fluconazole, itraconazole, and voriconazole against Acanthamoeba castellanii and Acanthamoeba polyphaga and assess their potential as therapeutic agents against Acanthamoeba infections in humans. Amebicidal activities of the triazoles were assessed by in vitro minimum inhibition concentration (MIC) determinations using trophozoites of A. castellanii and A. polyphaga. In addition, triazole effectiveness was assessed by ligand binding studies and inhibition of CYP51 activity of purified A. castellanii CYP51 (AcCYP51) that was heterologously expressed in Escherichia coli.

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Section: Discussionmentioning

confidence: 58%

Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14α-Demethylase (CYP51)

Lamb

Warrilow

Rolley

et al. 2015

Antimicrob Agents Chemother

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“…The identity of the other steroid was determined to be 24 (28) (17). In the related soil amoebae Acanthamoeba and Naegleria, both cyclopropyl steroids and several 24-desalkyl and 24-alkyl lanost-9-enols have been described (38,39).…”

Section: Resultsmentioning

confidence: 99%

Sterol phylogenesis and algal evolution.

Nes¹,

Norton²,

Crumley³

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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The stereochemistry of several sterol precursors and end products synthesized by two fungal-like microorganisms Prototheca wickerhamii (I) and Dictyostelium discoideum (H) have been determined by chromatographic (TLC, GLC, and HPLC) and spectral (UV, MS,-and 'H NMR) methods. From I and H the following sterols were isolated from the cells : cycloartenol, cyclolaudenol, 24(28)-methylenecycloartanol, ergosterol, protothecasterol, 4a-methylergostanol, 4a-methylclionastanol, clionastanol, 2413-ethylcholesta-8,22-enol, and dictyosterol. In addition, the mechanism of C-24 methylation was investigated in both organisms by feeding to I[2-3H]lanosterol, [2-3H] Based on what is known in the literature regarding sterol distribution and phylogenesis together with our rmdings that the stereochemical outcome of squalene oxide cyclization leads to the production of cycloartenol rather than lanosterol (characteristic of the fungal genealogy) and the chirality of the C-24 alkyl group is similar in the two nonphotosynthetic microbes (Ji oriented), we conclude that Prototheca is an apoplastic Chlorelia (i.e., an alga) and that Dictyostelium as well as the other soil amoebae that synthesize cycloartenol evolved from algal rather than fungal ancestors.The sterol pathway is thought to be very ancient, perhaps having arisen during the later stages of prokaryote evolution (1, 2). True sterols-e.g., end products such as cholesterolare antedated by the production of sterol-like compoundse.g., pentacyclic triterpenoids (3-6)-which were formed in the Precambrian anaerobic environment by the cyclization of squalene. Once molecular oxygen was in sufficient quantity in the atmosphere to permit squalene oxide genesis, a switching mechanism became operative to divert squalene from pentacyclic triterpenoid production to sterol synthesis (6, 7). The first compounds derived by the anaerobic cyclization of squalene oxide are the tetracyclic stereoisomers cycloartenol and lanosterol. Neither stereoisomer is known to be formed by cyclization in the same organism, whether the latter is a prokaryote or a eukaryote (2). This bifurcation in the sterol pathway is now recognized in biochemical textbooks (8-10) and in reviews on evolution (11-13) as a means to dissociate groups of organisms with an evolutionary history of oxygenic photosynthesis-e.g., as detected through the stereospecific formation of cycloartenol and its further metabolism of the 96,19-cyclopropyl ring-from those nonphotosynthetic progenitors and their descendants, which possess a lanosterolbased pathway (2). The association of the cycloartenol route and the endosymbiotic origin and subsequent loss of the chloroplast in some nonphotosynthetic systems is not clear. The biosynthesis of cycloartenol occurs in microsomes (14) and proceeds when the chloroplast is absent (15-18). In neither case is the biosynthesis of the stereoisomer influenced by the structure of the functional steroid at the end of the pathway, and their occurrence is not influenced by the molecular clock or mutatio...

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“…This is not a surprising finding, given that Balamuthia is a close relative of Acanthamoeba and ergosterol is known to be a major sterol membrane component of Acanthamoeba (11,17). These studies suggested that the ergosterol biosynthesis pathway may be a potential target in the rational development of therapeutic interventions against B. mandrillaris infections.…”

mentioning

confidence: 90%

“…Thus, a complete understanding of B. mandrillaris encystment and identification of compounds that can interfere with the encystment process should be of value in the improved treatment of BAE. Given that B. mandrillaris is a close relative of Acanthamoeba (2), it may contain similar membrane sterols, i.e., ergosterol and its precursor cycloartenol and ergosterollike sterols (11,17). This is supported by findings that ketoconazole, a preferential inhibitor of ergosterol biosynthesis (5), exhibits amoebastatic effects on B. mandrillaris in vitro (14) and BAE patients showed some response to this compound (3).…”

mentioning

confidence: 99%

Effect of Antimicrobial Compounds on Balamuthia mandrillaris Encystment and Human Brain Microvascular Endothelial Cell Cytopathogenicity

Siddiqui

Matin

Warhurst

et al. 2007

Antimicrob Agents Chemother

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Cycloheximide, ketoconazole, or preexposure of organisms to cytochalasin D prevented Balamuthia mandrillaris-associated cytopathogenicity in human brain microvascular endothelial cells, which constitute the bloodbrain barrier. In an assay for inhibition of cyst production, these three agents prevented the production of cysts, suggesting that the biosynthesis of proteins and ergosterol and the polymerization of actin are important in cytopathogenicity and encystment.

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Sterol biosynthesis de nova via cycloartenol by the soil amoeba Acanthamoeba polyphaga

Cited by 51 publications

References 51 publications

Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14α-Demethylase (CYP51)

Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14α-Demethylase (CYP51)

Sterol phylogenesis and algal evolution.

Effect of Antimicrobial Compounds on Balamuthia mandrillaris Encystment and Human Brain Microvascular Endothelial Cell Cytopathogenicity

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