Traynor Aimee M, Sheridan Kevin J, Jones Gary W, Calera José A, Doyle Sean
Department of Biology, Maynooth University, Maynooth, Ireland.
Centre for Biomedical Science Research, School of Clinical and Applied Sciences, Leeds Beckett University, Leeds, United Kingdom.
Front Microbiol. 2019 Dec 13;10:2859. doi: 10.3389/fmicb.2019.02859. eCollection 2019.
Fungal sulfur uptake is required for incorporation into the sidechains of the amino acids cysteine and methionine, and is also essential for the biosynthesis of the antioxidant glutathione (GSH), -adenosylmethionine (SAM), the key source of methyl groups in cellular transmethylation reactions, and -adenosylhomocysteine (SAH). Biosynthesis of redox-active gliotoxin in the opportunistic fungal pathogen has been elucidated over the past 10 years. Some fungi which produce gliotoxin-like molecular species have undergone unexpected molecular rewiring to accommodate this high-risk biosynthetic process. Specific disruption of gliotoxin biosynthesis, via deletion of , which encodes a γ-glutamyl cyclotransferase, leads to elevated intracellular antioxidant, ergothioneine (EGT), levels, and confirms crosstalk between the biosynthesis of both sulfur-containing moieties. Gliotoxin is ultimately formed by gliotoxin oxidoreductase GliT-mediated oxidation of dithiol gliotoxin (DTG). In fact, DTG is a substrate for both GliT and a -thiomethyltransferase, GtmA. GtmA converts DTG to bisdethiobis(methylthio)gliotoxin (BmGT), using 2 mol SAM and resultant SAH must be re-converted to SAM via the action of the Methyl/Met cycle. In the absence of GliT, DTG fluxes via GtmA to BmGT, which results in both SAM depletion and SAH overproduction. Thus, the negative regulation of gliotoxin biosynthesis via GtmA must be counter-balanced by GliT activity to avoid Methyl/Met cycle dysregulation, SAM depletion and consequences on global cellular biochemistry in . DTG also possesses potent Zn chelation properties which positions this sulfur-containing metabolite as a putative component of the Zn homeostasis system within fungi. EGT plays an essential role in high-level redox homeostasis and its presence requires significant consideration in future oxidative stress studies in pathogenic filamentous fungi. In certain filamentous fungi, sulfur is additionally indirectly required for the formation of EGT and the disulfide-bridge containing non-ribosomal peptide, gliotoxin, and related epipolythiodioxopiperazines. Ultimately, interference with emerging sulfur metabolite functionality may represent a new strategy for antifungal drug development.
真菌摄取硫是将其掺入半胱氨酸和甲硫氨酸侧链所必需的，对于抗氧化剂谷胱甘肽（GSH）、S-腺苷甲硫氨酸（SAM，细胞转甲基化反应中甲基的关键来源）以及S-腺苷高半胱氨酸（SAH）的生物合成也至关重要。在过去10年里，人们已经阐明了机会性真菌病原体中具有氧化还原活性的Gliotoxin的生物合成过程。一些产生Gliotoxin样分子种类的真菌经历了意想不到的分子重排，以适应这种高风险的生物合成过程。通过缺失编码γ-谷氨酰环转移酶的基因来特异性破坏Gliotoxin的生物合成，会导致细胞内抗氧化剂麦角硫因（EGT）水平升高，并证实了两种含硫部分生物合成之间的相互作用。Gliotoxin最终由Gliotoxin氧化还原酶GliT介导的二硫醇Gliotoxin（DTG）氧化形成。事实上，DTG是GliT和一种α-硫甲基转移酶GtmA的底物。GtmA利用2摩尔SAM将DTG转化为双去硫双（甲硫基）Gliotoxin（BmGT），生成的SAH必须通过甲基/蛋氨酸循环的作用重新转化为SAM。在没有GliT的情况下，DTG通过GtmA流向BmGT，这会导致SAM消耗和SAH过量产生。因此，GliT的活性必须对GtmA对Gliotoxin生物合成的负调控进行平衡，以避免甲基/蛋氨酸循环失调、SAM消耗以及对真菌整体细胞生物化学的影响。DTG还具有强大的锌螯合特性，这使得这种含硫代谢物成为真菌锌稳态系统的一个假定组成部分。EGT在高水平的氧化还原稳态中起着至关重要的作用，在未来对致病性丝状真菌的氧化应激研究中，其存在需要得到充分考虑。在某些丝状真菌中，硫对于EGT以及含二硫键的非核糖体肽Gliotoxin和相关的表硫代二氧哌嗪的形成也是间接必需的。最终，干扰新兴硫代谢物的功能可能代表了一种抗真菌药物开发的新策略。
