Harzianopyridone

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.

This study explains the scarce information on the role of harzianopyridone (HZRP) in the alleviation of chromium (Cr) stress alleviation in Vigna radiata (L.). To this end, V. radiata seedlings primed with HZRP at 1 and 2 ppm were exposed to 50 mg kg-1 Cr for 30 days. Cr stress reduced growth, chlorophyll (Chl) content, net photosynthetic rate, gas-exchange attributes along with enhanced oxidative damages, i.e., electrolyte leakage (EL), hydrogen peroxide (H2O2), and malondialdehyde (MDA). Application of HZRP enhanced intercellular carbon dioxide (CO2) concentration, stomatal conductance, and net photosynthetic rate with decreased activity of the chlorophyllase (Chlase) enzyme in V. radiata seedlings exposed to Cr stressed conditions. To maintain Cr-induced oxidative damages, HZRP treatment increased the levels of antioxidant metabolites (phenolic and flavonoids) and the activity of antioxidative enzymes [superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD)] in V. radiata seedlings grown in normal and Cr-polluted potted soil. In addition to this, glycine betaine content was also increased in plants grown in Cr-contaminated soil. It is proposed the potential role of supplementation of HZRP in mitigating Cr stress. Further research should be conducted to evaluate the potential of HZRP in the mitigation of abiotic stresses in plants.

A Krebs cycle intermediate metabolite, itaconate, has gained attention as a potential antimicrobial and autoimmune disease treatment due to its anti-inflammatory effects. While itaconate and its derivatives pose an attractive therapeutic option for the treatment of inflammatory diseases, the effects outside the immune system still remain limited, particularly in the muscle. Therefore, we endeavored to determine if itaconate signaling impacts muscle differentiation. Utilizing the well-established C2C12 model of in vitro myogenesis, we evaluated the effects of itaconate and its derivatives on transcriptional and protein markers of muscle differentiation as well as mitochondrial function. We found itaconate and the derivatives dimethyl itaconate and 4-octyl itaconate disrupt differentiation media-induced myogenesis. A primary biological effect of itaconate is a succinate dehydrogenase (SDH) inhibitor. We find the SDH inhibitors dimethyl malonate and harzianopyridone phenocopie the anti-myogenic effects of itaconate. Furthermore, we find treatment with exogenous succinate results in blunted myogenesis. Together our data indicate itaconate and its derivatives interfere with in vitro myogenesis, potentially through inhibition of SDH and subsequent succinate accumulation. We also show 4-octyl itaconate suppresses injury-induced MYOG expression in vivo. More importantly, our findings suggest the therapeutic potential of itaconate, and its derivatives could be limited due to deleterious effects on myogenesis.