2022
DOI: 10.1021/acs.orglett.2c02396
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Discovery of Oxidized Polycyclic Tetramate Macrolactams Bearing One or Two Rings through Combinatorial Pathway Reassembly

Abstract: The structural diversity of polycyclic tetramate macrolactams (PoTeMs) are mainly generated by the cyclases and cytochrome P450s (CYPs). The PoTeM cluster sah in Saccharopolyspora hirsuta harboring two CYP genes was combinatorially reassembled and heterologously expressed in Streptomyces. As a result, six new cytotoxic PoTeMs, sahamides A−F (1−6), were discovered, and 1−3 are the first examples of oxidized one-ring PoTeMs. Remarkably, SahE represents the first CYP performing oxidative modification on the ornit… Show more

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Cited by 6 publications
(9 citation statements)
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“…ZJ306, [10b] PDB ID 8JOO) and CftA (from Streptomyces torulosus NRRL B‐3889, [15] PDB ID 8JNP), at the resolutions of 2.0 and 2.25 Å, respectively (data collection and refinement statistics are available in Table S1). Consistent with previous reports, [14a,e] IkaD catalyzed the conversion of 1 to 1 a (epoxidation of C7=C8) and then to 1 b (hydroxylation at C29); while CftA transformed 1 to 1 c (ketonization at C29) and then to 1 d (hydroxylation at C30) (Figure 1C). IkaD and CftA exhibit typical triangular fold of P450 enzymes (Figure 2A).…”
Section: Resultssupporting
confidence: 92%
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“…ZJ306, [10b] PDB ID 8JOO) and CftA (from Streptomyces torulosus NRRL B‐3889, [15] PDB ID 8JNP), at the resolutions of 2.0 and 2.25 Å, respectively (data collection and refinement statistics are available in Table S1). Consistent with previous reports, [14a,e] IkaD catalyzed the conversion of 1 to 1 a (epoxidation of C7=C8) and then to 1 b (hydroxylation at C29); while CftA transformed 1 to 1 c (ketonization at C29) and then to 1 d (hydroxylation at C30) (Figure 1C). IkaD and CftA exhibit typical triangular fold of P450 enzymes (Figure 2A).…”
Section: Resultssupporting
confidence: 92%
“…However, other carbons of the 5/6/5‐tricyclic ring systems, including C8, are far away from the Fe center. These observations can explain the dominant oxidation at C29 and the minor oxidation at C30 of 1 by CftA [14a] . Interestingly, in the CftA/ 1 complex, the pro ‐S and pro ‐R hydrogen atoms of C29 are almost equidistant from the heme iron (3.46 Å vs 3.4 Å, Figure 3D).…”
Section: Resultsmentioning
confidence: 87%
“…The other main branch featured several subclades of CYP107 P450s with known biosynthetic roles, including CftA ( II , clifednamides) (6, 20), IkaD ( VII.a , ikarugamycin epoxide) (26), Mg1D ( III , combamides B and G) (22), and CbmD ( VI , combamides) (30). Other prominent subclades featured characterized CYP105 family members ( IX , X ; SahD and SahE of sahamide biosynthesis) (10), yet-uncharacterized CYP450s likely acting in PTM biosynthesis due to gene clustering ( IV , V , VII.b , VIII ), plus BGC proximity-flagged ones (e.g., BE133 CYP(2)). Finally, some Kitasatospora CYP450s [ Kspr CYP(2)] upstream of Group 4 BGCs were considerably diverged from other members of this branch.…”
Section: Resultsmentioning
confidence: 99%
“…Examples include anti-inflammatory (27), antifungal (2), antibacterial (28), and predicted anticancer (29) activities, making the family compelling for future pharmaceutical and crop protective investigation. PTM BGCs are often targeted for synthetic refactoring to create new chemical matter or to probe their transcriptional regulation towards increasing production (10,18,22,24,(30)(31)(32).…”
Section: Introductionmentioning
confidence: 99%
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