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This macrolide is a result of a hybrid polyketide synthase (PKS)\u2010nonribosomal peptide synthetase (NRPS) assembly line that utilizes (2<jats:italic>S<\/jats:italic>)\u20102\u2010ethylmalonamyl as a starter unit. Here, we report that the formation and loading of this starter unit in the SFA assembly line involve two unusual enzymatic reactions that occur on a discrete acyl carrier protein (ACP), SfaO. An amide synthetase, SfaP, catalyzes the amidation of (2<jats:italic>S<\/jats:italic>)\u20102\u2010ethylmalonyl in a SfaO\u2010dependent manner. Then, a \u03b2\u2010ketoacyl\u2010ACP synthase III\u2010like protein, SfaN, transfers resultant (2<jats:italic>S<\/jats:italic>)\u20102\u2010ethylmalonamyl from SfaO onto the loading ACP domain of the hybrid PKS\u2010NRPS assembly line to prime SFA biosynthesis. Both SfaP and SfaN display promiscuous activities. This study furthers the appreciation of assembly line chemistry, as a new paradigm for unusual building block formation and incorporation is provided.<\/jats:p>","DOI":"10.1002\/anie.202217090","type":"journal-article","created":{"date-parts":[[2023,4,7]],"date-time":"2023-04-07T07:16:25Z","timestamp":1680851785000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Formation and Loading of a (2<i>S<\/i>)\u20102\u2010Ethylmalonamyl Starter Unit in the Assembly Line of Polyketide\u2010Nonribosomal Peptide Hybrid Sanglifehrin A"],"prefix":"10.1002","volume":"62","author":[{"given":"Zhijun","family":"Tang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioorganic and Natural Products Chemistry Center for Excellence in Molecular Synthesis Shanghai Institute of Organic Chemistry Chinese Academy of Sciences  345 Lingling Road Shanghai 200032 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