8ovh | pdb_00008ovh
Crystal structure of O-acetyl-L-homoserine sulfhydrolase from Saccharomyces cerevisiae in complex with Pyridoxal-5'-phosphate
Structural highlights
FunctionCYSD_YEAST Catalyzes the conversion of O-acetyl-L-homoserine (OAH) into homocysteine in the methionine biosynthesis pathway (PubMed:7765825, PubMed:4609980, PubMed:795806, PubMed:36455053, PubMed:36379252). Required to efficiently reduce toxic levels of hydrogen sulfide generated when the sulfate assimilation pathway (SAP) is active (PubMed:36455053, PubMed:36379252). Also catalyzes the conversion of O-acetylserine (OAS) into cysteine, the last step in the cysteine biosynthesis pathway (PubMed:7765825, PubMed:4609980, PubMed:795806, PubMed:36455053). However, it seems that in S.cerevisiae cysteine biosynthesis occurs exclusively through the cystathionine pathway and not via direct incorporation of sulfur into OAS (PubMed:1732168). It therefore has no metabolic role in cysteine biosynthesis and may only have a regulatory role controlling OAS levels (PubMed:12586406).[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedChemical modification of small molecules is a key step for the development of pharmaceuticals. S-adenosyl-l-methionine (SAM) analogues are used by methyltransferases (MTs) to transfer alkyl, allyl and benzyl moieties chemo-, stereo- and regioselectively onto substrates, enabling an enzymatic way for specific derivatisation of a wide range of molecules. l-Methionine analogues are required for the synthesis of SAM analogues. Most of these are not commercially available. In nature, O-acetyl-l-homoserine sulfhydrolases (OAHS) catalyse the synthesis of l-methionine from O-acetyl-l-homoserine or l-homocysteine, and methyl mercaptan. Here, we investigated the substrate scope of ScOAHS from Saccharomyces cerevisiae for the production of l-methionine analogues from l-homocysteine and organic thiols. The promiscuous enzyme was used to synthesise nine different l-methionine analogues with modifications on the thioether residue up to a conversion of 75%. ScOAHS was combined with an established MT dependent three-enzyme alkylation cascade, allowing transfer of in total seven moieties onto two MT substrates. Ethylation was nearly doubled with the new four-enzyme cascade, indicating a beneficial effect of the in situ production of l-methionine analogues with ScOAHS. Enzymatic Synthesis of l-Methionine Analogues and Application in a Methyltransferase Catalysed Alkylation Cascade.,Mohr MKF, Saleem-Batcha R, Cornelissen NV, Andexer JN Chemistry. 2023 May 26:e202301503. doi: 10.1002/chem.202301503. PMID:37235813[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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