Caenorhabditis elegans is an important model used for many aspects of biological research. Its genome contains 76 genes coding for cytochromes P450 (P450s), and few data about the biochemical properties of those P450s have been published so far. However, an increasing number of articles have appeared on their involvement in the metabolism of xenobiotics and endobiotics such as fatty acid derivatives and steroids. Moreover, the implication of some P450s in various biological functions of C. elegans, such as survival, dauer formation, life span, fat content, or lipid metabolism, without mention of the precise reaction catalyzed by those P450s, has been reported in several articles. This review presents the state of our knowledge about C. elegans P450s.

Trichoderma spp. are cosmopolitan soil fungi that are highly resistant to many toxic compounds. Here, we show that Trichoderma virens and T. reesei are tolerant to aromatic amines (AA), a major class of pollutants including the highly toxic pesticide residue 3,4-dichloroaniline (3,4-DCA). In a previous study, we provided proof-of-concept remediation experiments in which another soil fungus, Podospora anserina , detoxifies 3,4-DCA through its arylamine N -acetyltransferase (NAT), a xenobiotic-metabolizing enzyme that enables acetyl coenzyme A-dependent detoxification of AA. To assess whether the N -acetylation pathway enables AA tolerance in Trichoderma spp., we cloned and characterized NATs from T. virens and T. reesei . We characterized recombinant enzymes by determining their catalytic efficiencies toward several toxic AA. Through a complementary approach, we also demonstrate that both Trichoderma species efficiently metabolize 3,4-DCA. Finally, we provide evidence that NAT-independent transformation is solely (in T. virens ) or mainly (in T. reesei ) responsible for the observed removal of 3,4-DCA. We conclude that T. virens and, to a lesser extent, T. reesei likely utilize another, unidentified, metabolic pathway for the detoxification of AA aside from acetylation. This is the first molecular and functional characterization of AA biotransformation in Trichoderma spp. Given the potential of Trichoderma for cleanup of contaminated soils, these results reveal new possibilities in the fungal remediation of AA-contaminated soil.

Methionine deprivation induces growth arrest and death of cancer cells. To eliminate L-methionine we produced, purified and characterized the recombinant pyridoxal 59-phosphate (PLP)-dependent L-methionine gamma-lyase MGL-BL929 from the cheese-ripening Brevibacterium aurantiacum. Transformation of an Escherichia coli strain with the gene BL929 from B. aurantiacum optimized for E. coli expression led to production of the MGL-BL929. Elimination of L-methionine and cytotoxicity in vitro were assessed, and methylation-sensitive epigenetics was explored for changes resulting from exposure of cancer cells to the enzyme. A bioreactor was built by encapsulation of the protein in human erythrocytes to achieve sustained elimination of L-methionine in extracellular fluids. Catalysis was limited to α,γ-elimination of L-methionine and L-homocysteine. The enzyme had no activity on other sulfur-containing amino acids. Enzyme activity decreased in presence of serum albumin or plasma resulting from reduction of PLP availability. Elimination of L-methionine induced cytotoxicity on a vast panel of human cancer cell lines and spared normal cells. Exposure of colorectal carcinoma cells to the MGL-BL929 reduced methyl-CpG levels of hyper methylated gene promoters including that of CDKN2A whose mRNA expression was increased, together with decrease in global histone H3-dimethyl lysine9. The MGL erythrocyte bioreactor durably preserves enzyme activity in vitro and strongly eliminates L-methionine from medium.

Proliferative glomerulonephritis is a severe condition that often leads to kidney failure. There is a significant lack of effective treatment for these disorders. Here, following the identification of a somatic PIK3CA gain-of-function mutation in podocytes of a patient, we demonstrate using multiple genetically engineered mouse models, single-cell RNA sequencing, and spatial transcriptomics the crucial role played by this pathway for proliferative glomerulonephritis development by promoting podocyte proliferation, dedifferentiation, and inflammation. Additionally, we show that alpelisib, a PI3Kα inhibitor, improves glomerular lesions and kidney function in different mouse models of proliferative glomerulonephritis and lupus nephritis by targeting podocytes. Surprisingly, we determined that pharmacological inhibition of PI3Kα affects B and T lymphocyte populations in lupus nephritis mouse models, with a decrease in the production of proinflammatory cytokines, autoantibodies, and glomerular complement deposition, which are all characteristic features of PI3Kδ inhibition, the primary PI3K isoform expressed in lymphocytes. Importantly, PI3Kα inhibition does not impact lymphocyte function under normal conditions. These findings were then confirmed in human lymphocytes isolated from patients with active lupus nephritis. In conclusion, we demonstrate the major role played by PI3Kα in proliferative glomerulonephritis and show that in this condition, alpelisib acts on both podocytes and the immune system.