ABHD5 suppresses cancer cell anabolism through lipolysis-dependent activation of the AMPK/mTORC1 pathway.

ABHD5 is an essential coactivator of ATGL, the rate-limiting triglyceride (TG) lipase in many cell types. Importantly, ABHD5 also functions as a tumor suppressor, and ABHD5 mRNA expression levels correlate with patient survival for several cancers. Nevertheless, the mechanisms involved in ABHD5-dependent tumor suppression are not known. We found that overexpression of ABHD5 induces cell cycle arrest at the G1 phase and causes growth retardation in a panel of prostate cancer cells. Transcriptomic profiling and biochemical analysis revealed that genetic or pharmacological activation of lipolysis by ABHD5 potently inhibits mTORC1 signaling, leading to a significant downregulation of protein synthesis. Mechanistically, we found that ABHD5 elevates intracellular AMP content, which activates AMPK, leading to inhibition of mTORC1. Interestingly, ABHD5-dependent suppression of mTORC1 was abrogated by pharmacological inhibition of DGAT1 or DGAT2, isoenzymes that re-esterify fatty acids in a process that consumes ATP. Collectively, this study maps out a novel molecular pathway crucial for limiting cancer cell proliferation, in which ABHD5-mediated lipolysis creates an energy-consuming futile cycle between TG hydrolysis and resynthesis, leading to inhibition of mTORC1 and cancer cell growth arrest.

Isolation and screening of carboxydotrophs isolated from composts and their potential for butanol synthesis.

Carboxydotrophs are known for their ability to convert carbon monoxide (CO) to butanol through fermentation. Such a platform offers a promising alternative approach to biofuel production from synthesis gas feedstocks. In this study, carboxydotrophs were isolated from various manure compost. Out of 500 isolates, only 11 carboxydotrophs (7 mesophiles and 4 thermophiles) were found to utilize CO as the sole source of carbon and energy. To assess the biochemical basis for their ability to produce biofuel (butanol), the level of activities of CO dehydrogenase (CODH), hydrogenase and butanol dehydrogenase (BDH) enzymes for these isolates against the known carboxydotroph, Butyribacterium methylotrophicum was assessed. All isolates showed evidence of enzyme activities (0.16-2.20 micromol min(-1)), with the majority exhibiting higher activities compared with the known carboxydotroph, B. methylotrophicum (0.33-0.71 micromol min(-1)). The level of activities for CODH and BDH ranged from 0.163-3.59 micromolmin(-1) and 0.19-2.2 micromolmin(-1), respectively. Three isolates (M7-1, T2-22, and T3-14) demonstrated enzymatic activity three to seven times higher than B. methylotrophicum. Of these, T2-22 exhibited the highest BDH activity and shows great promise in the conversion of toxic CO into butanol more so than other carboxytotrophs known thus far. This study revealed some biochemical basis for butanol production from CO by carboxydotrophs. However, more research is needed to discover a direct biological route for butanol production from CO to strengthen their potential for synthesis gas bioprocessing. Follow-up work will focus on whole-genome sequencing of the promising isolate T2-22 to provide system-level insights into how carboxydotrophs utilize and regulate their molecular machineries for butanol production.

Structural analysis, virtual screening and molecular simulation to identify potential inhibitors targeting 2'-O-ribose methyltransferase of SARS-CoV-2 coronavirus.

SARS-CoV-2, an emerging coronavirus, has spread rapidly around the world, resulting in over ten million cases and more than half a million deaths as of July 1, 2020. Effective treatments and vaccines for SARS-CoV-2 infection do not currently exist. Previous studies demonstrated that nonstructural protein 16 (nsp16) of coronavirus is an S-adenosyl methionine (SAM)-dependent 2'-O-methyltransferase (2'-O-MTase) that has an important role in viral replication and prevents recognition by the host innate immune system. In the present study, we employed structural analysis, virtual screening, and molecular simulation approaches to identify clinically investigated and approved drugs which can act as promising inhibitors against nsp16 2'-O-MTase of SARS-CoV-2. Comparative analysis of primary amino acid sequences and crystal structures of seven human CoVs defined the key residues for nsp16 2-O'-MTase functions. Virtual screening and docking analysis ranked the potential inhibitors of nsp16 from more than 4,500 clinically investigated and approved drugs. Furthermore, molecular dynamics simulations were carried out on eight top candidates, including Hesperidin, Rimegepant, Gs-9667, and Sonedenoson, to calculate various structural parameters and understand the dynamic behavior of the drug-protein complexes. Our studies provided the foundation to further test and repurpose these candidate drugs experimentally and/or clinically for COVID-19 treatment.Communicated by Ramaswamy H. Sarma.