Iterative Catalysis in the Biosynthesis of Mitochondrial Complex II Inhibitors Harzianopyridone and Atpenin B

Abstract

The pentasubstituted pyridine natural products harzianopyridone and atpenins are potent inhibitors of mitochondrial complex II. We identified the pathways of these compounds from their fungal producers and uncovered that the biosynthetic steps require multiple iterative enzymes. In particular, a methyltransferase and a flavin-dependent monooxygenase are used iteratively to introduce C5 and C6 methoxy groups. The pathway unexpectedly requires the installation and removal of an N-methoxy group, which is proposed to be a directing group that tunes the reactivity of the pyridone ring, possibly through the alpha effect.

Palladium‐Catalyzed Selective Carbofunctionalization of Inert γ‐C(sp3)−O Bonds with 4‐Hydroxypyridin‐2(1H)‐ones and 4‐Hydroxy‐2H‐pyran‐2‐ones

“…There has been considerable activity focused on the development of efficient and general methods for the construction of 4‐hydroxypyridin‐2( 1H )‐one and 4‐hydroxy‐ 2H ‐pyran‐2‐one because of their comprehensive pharmacological profiles such as anti‐tumor and antivirus activities. Among these, a strategy that uses 4‐hydroxypyridin‐2( 1H )‐one [2a–j] and 4‐hydroxy‐ 2H ‐pyran‐2‐one [2k] as the starting material has been demonstrated as an important strategy ascribed to its bi‐functional character. Consequently, development of efficient methods for the synthesis and structural modifications of 4‐hydroxypyridin‐2( 1H )‐ones and 4‐hydroxy‐ 2H ‐pyran‐2‐ones is still in urgent need.…”

Characterization of Highly Reductive Modification of Tetracycline D-Ring Reveals Enzymatic Conversion of Enone to Alkane

“…Therefore, these mechanisms which require the incorporation of a solvent-derived proton into products were invalidated. 31,32 Since the oxygen of carbonyl in β-hydroxyl-α,β-enone was easily exchanged with water oxygen, 33 the incubation of 15 and H 2 18 O resulted in the mass increment in + 2 Da and + 4 Da, indicating that both oxygens of 15 in C-10 and C-13 could exchange with H 2 18 O (Supplementary Fig. 12).…”

Molecular methods unravel the biosynthetic potential of Trichoderma species

“…[113][114][115][116] Until recently the BGC for 90 was unknown but its biosynthetic pathway was proposed based on the biosynthesis of other 2-pyridone natural products and on isotope feeding studies. 112 This proposal led to the identication of a candidate BGC from the genome of T. harzianum, a PKS-NRPS gene in addition to a potential ring expansion cytochrome P450 monooxygenase (P450 RE ) homologous to tenA. 112,113 Other tailoring enzymes were also encoded by the cluster such as: an additional P450; an ER; two FMO; a potential Nhydroxylase; and an O-MeT (Scheme 9).…”

“…112 This proposal led to the identication of a candidate BGC from the genome of T. harzianum, a PKS-NRPS gene in addition to a potential ring expansion cytochrome P450 monooxygenase (P450 RE ) homologous to tenA. 112,113 Other tailoring enzymes were also encoded by the cluster such as: an additional P450; an ER; two FMO; a potential Nhydroxylase; and an O-MeT (Scheme 9). The detailed biosynthetic pathway together with the function of each gene of the cluster were veried by heterologous expression of the genes in A. nidulans A1145 DEM, which revealed that four out of the six tailoring enzymes perform iterative catalysis.…”