{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T22:50:38Z","timestamp":1787957438747,"version":"build-2784847793"},"reference-count":39,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2010,6,23]],"date-time":"2010-06-23T00:00:00Z","timestamp":1277251200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biopolymers"],"published-print":{"date-parts":[[2010,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Nikkomycin Z is a dipeptide antifungal antibiotic characterized by two nonproteinogenic amino acids, nikkomycin C<jats:sub>Z<\/jats:sub> and 4\u2010(4\u2032\u2010hydroxy\u20102\u2032\u2010pyridinyl)\u2010homothreonine (HPHT). The HPHT scaffold is assembled by an aldol reaction between 2\u2010oxobutyrate and picolinaldehyde, the latter of which is derived from picolinic acid that is activated and loaded to coenzyme A by the aryl\u2010activating adenylation enzyme, NikE. We now provide evidence that NikE is also involved in the activation and loading of the \u03b1\u2010keto acid precursor, 4\u2010(2\u2032\u2010pyridinyl)\u20102\u2010oxo\u20104\u2010hydroxyisovalerate (POHIV), to a phosphopantetheinyl group of an acyl carrier protein domain of NikT. POHIV was synthesized using <jats:italic>Escherichia coli<\/jats:italic> 2\u2010dehydro\u20103\u2010deoxy\u2010phosphogluconate aldolase, and phenylalanine dehydrogenase from <jats:italic>Bacillus<\/jats:italic> sp. NRRL B\u201014911 was used to prepare the \u03b1\u2010amino acid, 4\u2010(2\u2032\u2010pyridinyl)\u2010homothreonine (PHT). Using the carboxylic acid\u2010dependent, ATP\u2010[<jats:sup>32<\/jats:sup>P]PP<jats:sub>i<\/jats:sub> exchange assay, NikE is shown to activate both picolinic acid and POHIV but not PHT. Furthermore, NikE loads POHIV to holo\u2010NikT to generate a new thioester\u2010linked intermediate, which was not observed using a NikT(S33A) mutant. Thus, NikE activates two distinct carboxylic acids to form two new thioester intermediates, one of which is subsequently reduced to the aldehyde and the other that likely serves as a substrate for the aminotransferase domain of NikT prior to condensation with nikkomycin C<jats:sub>Z<\/jats:sub> to yield the dipeptide. \u00a9 2010 Wiley Periodicals, Inc. 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