Figure 1. Early covalent drugs. a) The mechanism of action of aspirin. b) COX-1 active site serine and its covalenta dduct after its reaction with c) ab romo derivativeofa spirin. d) The mechanism of action of penicillin.e )Co-crystal structureofD D-transpeptidase bound covalently with ampicillin (PDB ID:5HL9). f) The ampicillin-serine complex in the active site of DD-transpeptidase. g) The mechanism of actiono fa cetaminophen.

The eukaryotic thiamin pyrimidine synthase, THI5p, has been identified as a suicidal/single-turnover enzyme that catalyzes the conversion of its active site histidine and lysine-bound pyridoxal phosphate (PLP) to the thiamin pyrimidine (HMP-P).Here we identify the histidine and PLP fragments using bottom-up proteomics and LC-MS analysis. We also identify the active form of the iron cofactor and quantitate the oxygen requirement of the THI5p reaction. This information is integrated into a mechanistic proposal for this remarkable reaction.

Construction of structurally diverse carbazoles and bis-carbazoles by protecting-group-free formal [4 + 2]-benzannulation of 2-alkenyl indoles and aldehydes is demonstrated.

The yeast thiamin pyrimidine synthase THI5p catalyzes one of the most complex organic rearrangements found in primary metabolism. In this reaction, the active site His66 and PLP are converted to thiamin pyrimidine in the presence of Fe­(II) and oxygen. The enzyme is a single-turnover enzyme. Here, we report the identification of an oxidatively dearomatized PLP intermediate. We utilize oxygen labeling studies, chemical-rescue-based partial reconstitution experiments, and chemical model studies to support this identification. In addition, we also identify and characterize three shunt products derived from the oxidatively dearomatized PLP.

The Cover Feature shows notable covalent inhibitors and structures of their complexes with protein targets. Covalent inhibitors involve mainly electrophilic functional groups to form covalent adducts with nucleophilic amino acid residues in protein targets. These functional groups include electrodeficient alkene, nitrile, lactone, lactam, expoxide, alkylhalide, etc.. A notable exception are thiol‐containing compounds that are redox active to conjugate to cysteines in proteins. More information can be found in the Review by Wenshe Liu et al. on page 889 in Issue 9, 2019 (DOI: 10.1002/cmdc.201900107).