Acidic pH irreversibly activates the signaling enzyme SARM1 was written by Zhao, Yong Juan;He, Wei Ming;Zhao, Zhi Ying;Li, Wan Hua;Wang, Qian Wen;Hou, Yun Nan;Tan, Yongjun;Zhang, Dapeng. And the article was included in FEBS Journal in 2021.Name: ((2R,3S,4R,5R)-5-(3-Carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate The following contents are mentioned in the article:
SARM1, an executioner in axon degeneration, is an autoinhibitory NAD-consuming enzyme, composed of multiple domains. NMN and its analogs, CZ-48 and VMN, are the only known activators, which can release the inhibitory ARM domain from the enzymic TIR domain. Here, we document that acid can also activate SARM1, even more efficiently than NMN, possibly via the protonation of the neg. residues. Systematic mutagenesis revealed that a single mutation, E689Q in TIR, led to the constitutive activation of SARM1. It forms a salt bridge with R216 in the neighboring ARM, maintaining the autoinhibitory structure. Using this ‘acid activation’ protocol, mutation K597E was found to inhibit activation, while H685A eliminated SARM1 catalytic activity, revealing two distinct inhibitory mechanisms. The protocol has also been applied to differentiate two classes of chem. inhibitors. NAD, dHNN, disulfiram, CHAPS, and TRX-100 mainly inhibited the activation process, while nicotinamide and Tweens mainly inhibited SARM1 catalysis. Taken together, we demonstrate a new mechanism for SARM1 activation and decipher two distinct inhibitory mechanisms of SARM1. This study involved multiple reactions and reactants, such as ((2R,3S,4R,5R)-5-(3-Carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate (cas: 1094-61-7Name: ((2R,3S,4R,5R)-5-(3-Carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate).
((2R,3S,4R,5R)-5-(3-Carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate (cas: 1094-61-7) belongs to amides. Amides can be viewed as a derivative of a carboxylic acid RC(=O)OH with the hydroxyl group –OH replaced by an amine group −NR′R″; or, equivalently, an acyl (alkanoyl) group RC(=O)− joined to an amine group. Ionic, or saltlike, amides are strongly alkaline compounds ordinarily made by treating ammonia, an amine, or a covalent amide with a reactive metal such as sodium.Name: ((2R,3S,4R,5R)-5-(3-Carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen phosphate
Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics