ADVERTISEMENT
2 /3 FREE ARTICLES LEFT THIS MONTH Remaining
Chemistry matters. Join us to get the news you need.

If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.

ENJOY UNLIMITED ACCES TO C&EN

Synthesis

Enzyme’s Elusive Proton Donor Found

Enzyme Mechanisms: Active-site tyrosine is found to transfer the needed proton in enoyl-thioester reductase reactions

by Stu Borman
April 20, 2015 | APPEARED IN VOLUME 93, ISSUE 16

Researchers have identified the long-sought proton donor in enoyl-thioester reductase (ETR) enzymes, enabling them to reengineer the stereochemistry of the enzymes’ catalytic action. The work has implications for polyketide synthase-based synthesis of natural products and natural-product-like compounds because related reductases are major components of polyketide synthase enzyme complexes. In reactions catalyzed by ETRs, a proton from an active-site amino acid or water molecule is transferred to the α-carbon of the enoyl-thioester substrate. But scientists haven’t been able to pin down the identity of the proton donor. Tobias J. Erb of the Max Planck Institute for Terrestrial Microbiology, in Marburg, Germany, and coworkers provided experimental evidence for an earlier proposal that an intermediate called a C2-ene adduct forms between the substrate and NADPH in the reaction, suggesting it might be involved in the proton-transfer process. Erb and coworkers’ use of this C2-ene adduct as a molecular probe of the reaction has now enabled them to identify an active-site tyrosine as the elusive proton donor (Nat. Chem. Biol. 2015, DOI: 10.1038/nchembio.1794). This new understanding also enabled them to reengineer the enzyme to catalyze the reaction with inverted stereochemistry.

09316-scicon-partialmech-690.jpg
In an ETR-catalyzed reaction, a C2-ene adduct (left) splits (leaving-group not shown) to produce an enolate intermediate (center), which accepts a proton (red) from an active-site tyrosine, yielding a butyryl-CoA species (right).
X

Article:

This article has been sent to the following recipient:

Leave A Comment

*Required to comment