Novel Cysteine-Centered Sulfur Metabolic Pathway in the Thermotolerant Methylotrophic Yeast Hansenula polymorpha

Abstract

In yeast and filamentous fungi, sulfide can be condensed either with O-acetylhomoserine to generate homocysteine, the precursor of methionine, or with O-acetylserine to directly generate cysteine. The resulting homocysteine and cysteine can be interconverted through transsulfuration pathway. Here, we systematically analyzed the sulfur metabolic pathway of the thermotolerant methylotrophic yeast Hansenula polymorpha, which has attracted much attention as an industrial yeast strain for various biotechnological applications. Quite interestingly, the detailed sulfur metabolic pathway of H. polymorpha, which was reconstructed based on combined analyses of the genome sequences and validation by systematic gene deletion experiments, revealed the absence of de novo synthesis of homocysteine from inorganic sulfur in this yeast. Thus, the direct biosynthesis of cysteine from sulfide is the only pathway of synthesizing sulfur amino acids from inorganic sulfur in H. polymorpha, despite the presence of both directions of transsulfuration pathway Moreover, only cysteine, but no other sulfur amino acid, was able to repress the expression of a subset of sulfur genes, suggesting its central and exclusive role in the control of H. polymorpha sulfur metabolism. 35S-Cys was more efficiently incorporated into intracellular sulfur compounds such as glutathione than 35S-Met in H. polymorpha, further supporting the cysteine-centered sulfur pathway. This is the first report on the novel features of H. polymorpha sulfur metabolic pathway, which are noticeably distinct from those of other yeast and filamentous fungal species.

Distinct roles of two cytoplasmic thioredoxin reductases (Trr1/2) in the redox system involving cysteine synthesis and host infection of Beauveria bassiana

“…Error bars: SD from three replicates restoration of the severe growth defects displayed by the mentioned six mutants in CZA. In some model fungi, sulfate can be sequentially catalyzed to sulfite, sulfide, and cysteine (Cherest and Surdin-Kerjan 1992;Marzluf 1997;Sohn et al 2014). Cysteine can also form from methionine transformation or glutathione decomposition (Sohn et al 2014).…”

“…In some model fungi, sulfate can be sequentially catalyzed to sulfite, sulfide, and cysteine (Cherest and Surdin-Kerjan 1992;Marzluf 1997;Sohn et al 2014). Cysteine can also form from methionine transformation or glutathione decomposition (Sohn et al 2014). For this reason, three intermediate products in the pathway of cysteine biosynthesis were tested for their effects on the auxotrophic phenotype attributed to the trr1 deletion.…”

Hansenula polymorpha Pmt4p Plays Critical Roles in O-Mannosylation of Surface Membrane Proteins and Participates in Heteromeric Complex Formation

“…This was accompanied with inactivation of the chromosomal wild-type PMT4 allele. Expression of the PMT4 conditional allele could be down-regulated by the controllable HpMET3 promoter, whose expression is repressed by the supplementation of cysteine but is induced under sulfur-limited conditions [ 56 ]. The growth of the Hppmt1 Δ [P MET3 - PMT4 ] mutant strain was severely retarded on SD medium containing more than 2 mM cysteine, compared to that of the Hppmt1∆ single mutant ( Fig 4A and 4B ).…”

A Novel Mitochondrial Serine O-Acetyltransferase, OpSAT1, Plays a Critical Role in Sulfur Metabolism in the Thermotolerant Methylotrophic Yeast Ogataea parapolymorpha

“…The OAS pathway is also reported in certain fungal species 13 , 14 . However, in yeast and fungal species, cysteine biosynthesis can be also achieved independently from the OAS pathway.…”