Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human genetic enzymopathies, is caused by over 160 different point mutations and contributes to the severity of many acute and chronic diseases associated with oxidative stress, including hemolytic anemia and bilirubin-induced neurological damage particularly in newborns. As no medications are available to treat G6PD deficiency, here we seek to identify a small molecule that corrects it. Crystallographic study and mutagenesis analysis identify the structural and functional defect of one common mutant (Canton, R459L). Using high-throughput screening, we subsequently identify AG1, a small molecule that increases the activity of the wild-type, the Canton mutant and several other common G6PD mutants. AG1 reduces oxidative stress in cells and zebrafish. Furthermore, AG1 decreases chloroquine- or diamide-induced oxidative stress in human erythrocytes. Our study suggests that a pharmacological agent, of which AG1 may be a lead, will likely alleviate the challenges associated with G6PD deficiency.

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We study the hydrogenation of CO under ambient pressure conditions over a Co-MnO x model catalyst using chemical transient kinetics (CTK) under calibrated molecular flow conditions. Alkanes and alkenes are shown to form with markedly differing kinetics. Quantitation of the data allows accumulating carbon and oxygen coverages to be determined at any instant of the “buildup” transients. Anderson–Schulz–Flory (ASF) chain lengthening probabilities are evaluated while approaching the steady-state of the reaction. A linear dependence of these probabilities on the transient CO gas pressure provides evidence for a CO insertion mechanism being in operation under high-coverage conditions. A detailed kinetic analysis of reactant/product formation and scavenging is in agreement with this conclusion. However, for coverages below the monolayer limit, fast CO dissociation, probably hydrogen-assisted and promoted by Mn2+, also enables significant CH x –CH y coupling to occur. Evidence was obtained from high resolution transmission electron microscopy (HRTEM) that a phase transition from Co to Co2C was triggered under atmospheric pressure conditions for the Co-MnO x catalyst.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common blood disorder, presenting multiple symptoms, including hemolytic anemia. It affects 400 million people worldwide, with more than 160 single mutations reported in G6PD. The most severe mutations (about 70) are classified as class I, leading to more than 90% loss of activity of the wild-type G6PD. The crystal structure of G6PD reveals these mutations are located away from the active site, concentrating around the noncatalytic NADP+-binding site and the dimer interface. However, the molecular mechanisms of class I mutant dysfunction have remained elusive, hindering the development of efficient therapies. To resolve this, we performed integral structural characterization of five G6PD mutants, including four class I mutants, associated with the noncatalytic NADP+ and dimerization, using crystallography, small-angle X-ray scattering (SAXS), cryogenic electron microscopy (cryo-EM), and biophysical analyses. Comparisons with the structure and properties of the wild-type enzyme, together with molecular dynamics simulations, bring forward a universal mechanism for this severe G6PD deficiency due to the class I mutations. We highlight the role of the noncatalytic NADP+-binding site that is crucial for stabilization and ordering two β-strands in the dimer interface, which together communicate these distant structural aberrations to the active site through a network of additional interactions. This understanding elucidates potential paths for drug development targeting G6PD deficiency.

We recently identified AG1, as mall-molecule activatort hat functions by promoting oligomerization of glucose-6-phosphate dehydrogenase (G6PD) to the catalytically competent forms. Biochemical experiments indicatet hat the activation of G6PD by the original hit molecule (AG1) is noncovalent and that one C 2 -symmetric region of the G6PD homodimer is important for ligand function. Consequently,t he disulfide in AG1 is not required for activationo fG 6PD, and an umber of analogues were prepared without this reactive moiety.O ur study supports am echanism of action whereby AG1 bridges the dimer interface at the structuraln icotinamide adenine dinucleotide phosphate (NADP + )b inding sites of two interacting G6PD monomers. Smallm olecules that promoteG 6PD oligomerization have the potential to provide af irst-in-class treatment for G6PD deficiency. Thisg eneral strategy could be applied to othere nzymed eficienciesi nw hichc ontrol of oligomerization can enhancee nzymatica ctivity and/or stability.

New reactions and reagents that allow for multiple bond-forming events per synthetic operation are required to achieve structural complexity and thus value with step-, time-, cost-, and waste-economy. Here we report a new class of reagents that function like tetramethyleneethane (TME), allowing for back-to-back [4 + 2] cycloadditions, thereby amplifying the complexity-increasing benefits of Diels–Alder and metal-catalyzed cycloadditions. The parent recursive reagent, 2,3-dimethylene-4-trimethylsilylbutan-1-ol (DMTB), is readily available from the metathesis of ethylene and THP-protected 4-trimethylsilylbutyn-1-ol. DMTB and related reagents engage diverse dienophiles in an initial Diels–Alder or metal-catalyzed [4 + 2] cycloaddition, triggering a subsequent vinylogous Peterson elimination that recursively generates a new diene for a second cycloaddition. Overall, this multicomponent catalytic cascade produces in one operation carbo- and heterobicyclic building blocks for the synthesis of a variety of natural products, therapeutic leads, imaging agents, and materials. Its application to the three step synthesis of a new solvatochromic fluorophore, N-ethyl(6-N,N-dimethylaminoanthracene-2,3-dicarboximide) (6-DMA), and the photophysical characterization of this fluorophore are described.

A chemical research program at a public high school has been developed. The full-year Advanced Chemical Research class (ACR) in the high school enrolls 20 to 30 seniors each year, engaging them in long-term experimental projects. Through partnerships involving university scientists, ACR high school students have had the opportunity to explore a number of highly sophisticated original research projects. As an example of the quality of experimental work made possible through these high school–university partnerships, this article describes the development of a novel method for the oxidation of ethidium bromide, a mutagen commonly used in molecular biology. Data collected from ACR alumni show that the ACR program is instrumental in encouraging students to pursue careers in scientific fields and in creating life-long problem-solvers.

Oxidative stress caused by infection, medication, food, and imbalance of metabolic cycles damages DNA and organelles, which may lead to cancer, blood disorders, and other serious diseases. Glucose‐6‐phosphate dehydrogenase (G6PD) is the rate‐limiting enzyme in the pentose phosphate pathway, which is essential for nucleotide, fatty acid, cholesterol, and hormone synthesis. In addition to those roles, G6PD reduces NADP+ to NADPH, which is crucial for reducing reactive oxygen species. Dysfunction of G6PD increases susceptibility to oxidative stress, especially in erythrocyte due to the lack of mitochondria, which is another source of NADPH. Interestingly, 400 million people worldwide have mutations on the g6pd gene, and the World Health Organization (WHO) has classified more than 160 missense mutations into five classes. The Class I G6PD deficiency is the most severe form; patients have less than 10% enzymatic activity of wild‐type G6PD and suffer from chronic non‐spherocytic hemolytic anemia. Here, we provide a new insight into the loss of activity in G6PD deficiency, based on the structure of the Class I pathogenic mutants of G6PD. We will discuss the structural basis of the Class I mutants of G6PD and its implications to various symptoms in G6PD deficiency. Support or Funding Information National Institutes of Health, R01 grant, HD084422; Japan Society for the Promotion of Science KAKENHI, Grant‐in Aid for Research Activity Start‐up, JP19K23713; University of Tsukuba; Stanford University; SLAC National Accelerator Laboratory