https://www.cell.com/cell/pdf/S0092-8674(05)00109-1.pdf

Mitochondria, Oxidants, and Aging

From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites

Emerging technologies allow the high-throughput profiling of metabolic status from a blood specimen (metabolomics) We investigated whether metabolite profiles could predict the development of diabetes Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes Amino acids, amines and other polar metabolites were profiled in baseline specimens by liquid chromatography-tandem mass spectrometry (LC-MS) Cases and controls were matched for age, body mass index and fasting glucose Five branched-chain and aromatic amino acids had highly significant associations with future diabetes: isoleucine, leucine, valine, tyrosine and phenylalanine A combination of three amino acids predicted future diabetes (with a more than fivefold higher risk for individuals in top quartile) The results were replicated in an independent, prospective cohort These findings underscore the potential key role of amino acid metabolism early in the pathogenesis of diabetes and suggest that amino acid profiles could aid in diabetes risk assessment

/pdf/metabolite-profiles-and-the-risk-of-developing-diabetes-4xvb1xzl5e.pdf

Metabolite profiles and the risk of developing diabetes

Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase

There have been many advances in our knowledge about different aspects of P2Y receptor signaling since the last review published by our International Union of Pharmacology subcommittee. More receptor subtypes have been cloned and characterized and most orphan receptors deorphanized, so that it is now possible to provide a basis for a future subdivision of P2Y receptor subtypes. More is known about the functional elements of the P2Y receptor molecules and the signaling pathways involved, including interactions with ion channels. There have been substantial developments in the design of selective agonists and antagonists to some of the P2Y receptor subtypes. There are new findings about the mechanisms underlying nucleotide release and ectoenzymatic nucleotide breakdown. Interactions between P2Y receptors and receptors to other signaling molecules have been explored as well as P2Y-mediated control of gene transcription. The distribution and roles of P2Y receptor subtypes in many different cell types are better understood and P2Y receptor-related compounds are being explored for therapeutic purposes. These and other advances are discussed in the present review.

https://pharmrev.aspetjournals.org/content/pharmrev/58/3/281.full.pdf

International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: From Molecular Mechanisms and Pathophysiology to Therapy

The citric acid cycle is central to the regulation of energy homeostasis and cell metabolism. Mutations in enzymes that catalyse steps in the citric acid cycle result in human diseases with various clinical presentations. The intermediates of the citric acid cycle are present at micromolar concentration in blood and are regulated by respiration, metabolism and renal reabsorption/extrusion. Here we show that GPR91 (ref. 3), a previously orphan G-protein-coupled receptor (GPCR), functions as a receptor for the citric acid cycle intermediate succinate. We also report that GPR99 (ref. 4), a close relative of GPR91, responds to alpha-ketoglutarate, another intermediate in the citric acid cycle. Thus by acting as ligands for GPCRs, succinate and alpha-ketoglutarate are found to have unexpected signalling functions beyond their traditional roles. Furthermore, we show that succinate increases blood pressure in animals. The succinate-induced hypertensive effect involves the renin-angiotensin system and is abolished in GPR91-deficient mice. Our results indicate a possible role for GPR91 in renovascular hypertension, a disease closely linked to atherosclerosis, diabetes and renal failure.

/pdf/citric-acid-cycle-intermediates-as-ligands-for-orphan-g-3bmebhrgov.pdf

Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors

In the presence of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), nucleophilic and reactive reagents are prevented from interacting with a rhodium carbene, allowing asymmetric cyclopropanation to occur with high yield and stereoselectivity on a variety of compounds. A high-throughput screen was conducted on cyclopropanation with a complementary catalytic system in the presence of 90 different poisonous nucleophiles and varying amounts of HFIP (10 equiv, used as reaction solvent). The scope of both the aryl/heteroaryl diazoacetate and the olefin was expanded, and the study culminated in the enantioselective functionalization of complex molecules including API and natural products. 

Hexafluoroisopropanol for the Selective Deactivation of Poisonous Nucleophiles Enabling Catalytic Asymmetric Cyclopropanation of Complex Molecules

Within the realm of drug discovery, high-throughput experimentation techniques enable the rapid optimization of reactions and expedited generation of drug compound libraries for biological and pharmacokinetic evaluation.  Herein we report the development of a segmented flow mass spectrometry-based platform to enable the rapid exploration of photoredox reactions for early-stage drug discovery.  Specifically, microwell plate-based photochemical reaction screens were reformatted to segmented flow format to enable delivery to nanoelectrospray ionization-mass spectrometry analysis. This approach was demonstrated for the late-stage modification of complex drug scaffolds, as well as the subsequent structure-activity relationship evaluation of synthesized analogs. This technology is anticipated to expand the robust capabilities of photoredox catalysis in drug discovery by enabling high-throughput library diversification.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/anie.202301664

Jinhai Gao

Papers

Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors

Hexafluoroisopropanol for the Selective Deactivation of Poisonous Nucleophiles Enabling Catalytic Asymmetric Cyclopropanation of Complex Molecules

High-Throughput Optimization of Photochemical Reactions using Segmented-Flow Nanoelectrospray-Ionization Mass Spectrometry.