The enzyme methyl-coenzyme M reductase (MCR) plays an important role in mediating global levels of methane by catalyzing a reversible reaction that leads to the production or consumption of this potent greenhouse gas in methanogenic and methanotrophic archaea. In methanogenic archaea, the alpha subunit of MCR (McrA) typically contains four to six posttranslationally modified amino acids near the active site. Recent studies have identified enzymes performing two of these modifications (thioglycine and 5-[S]-methylarginine), yet little is known about the formation and function of the remaining posttranslationally modified residues. Here, we provide in vivo evidence that a dedicated S-adenosylmethionine-dependent methyltransferase encoded by a gene we designated methylcysteine modification (mcmA) is responsible for formation of S-methylcysteine in Methanosarcina acetivorans McrA. Phenotypic analysis of mutants incapable of cysteine methylation suggests that the S-methylcysteine residue might play a role in adaption to mesophilic conditions. To examine the interactions between the S-methylcysteine residue and the previously characterized thioglycine, 5-(S)-methylarginine modifications, we generated M. acetivorans mutants lacking the three known modification genes in all possible combinations. Phenotypic analyses revealed complex, physiologically relevant interactions between the modified residues, which alter the thermal stability of MCR in a combinatorial fashion that is not readily predictable from the phenotypes of single mutants. High-resolution crystal structures of inactive MCR lacking the modified amino acids were indistinguishable from the fully modified enzyme, suggesting that interactions between the posttranslationally modified residues do not exert a major influence on the static structure of the enzyme but rather serve to fine-tune the activity and efficiency of MCR.
A facile synthetic route for the preparation of N-protected γ-amino β-keto esters from amino aldehydes and ethyl diazoacetate is described. The two component coupling is facilitated by tin(II) chloride followed by semipinacol rearrangement leading to the product in quantitative yield. The reaction is mild, instantaneous and compatible with Boc-, Fmoc- and Cbz-amino protecting groups.
Combination antiretroviral therapy is the mainstay of HIV treatment, lowering plasma viral levels below detection. However, eradication of HIV is a major challenge due to cellular and anatomical viral reservoirs that are often protected from treatment by efflux transporters, such as P-glycoprotein (P-gp) at the blood−brain barrier (BBB). Herein we described a Trojan horse approach to therapeutic evasion of P-gp based on a reversibly linked combination of HIV reverse transcriptase and protease inhibitors. Potent inhibition of P-gp efflux in cells, including human brain endothelial cells, was observed with the linked heterodimeric compounds. In vitro regeneration of active monomeric drugs was observed in a reducing environment with these dimeric prodrugs, with the superior leaving group promoting more facile release from the tether. These release trends were mirrored in the efficacy of the in cyto anti-HIV-1 activity of the Trojan horse heterodimers.
Significant differences in pregnancy rates and endometrial thickness were seen. Gonadotropin alone thus appears to give better results, but CC + Gonadotropin seems to be a cost-effective drug.
19Methyl-coenzyme M reductase (MCR) plays an important role in mediating 20 global levels of methane by catalyzing a reversible reaction that leads to the production or 21 consumption of this potent greenhouse gas in methanogenic and methanotrophic archaea. 22Although the methane-oxidizing activity of MCR in anaerobic methane-oxidizing 49 archaea (also referred to as ANME) leads to the consumption of ca. 90% of the methane 50 produced in marine sediments (3, 4), the methanogenic activity of MCR dominates, 51 leading to the net production of ca.
Tin(II) Chloride Assisted Synthesis of N-Protected γ-Amino β-Keto Esters Through Semipinacol Rearrangement. -The reaction tolerates -Boc, -Cbz and -Fmoc protecting groups and does not require an inert atmosphere. -(BANDYOPADHYAY, A.; AGRAWAL, N.; MALI, S. M.; JADHAV, S. V.; GOPI*, H. N.; Org. Biomol. Chem. 8 (2010) 21, 4855-4860, http://dx.
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