Identification of purine biosynthesis as an NADH-sensing pathway to mediate energy stress.

ABSTRACT: An enhanced NADH/NAD⁺ ratio, termed reductive stress, is associated with many diseases. However, whether a downstream sensing pathway exists to mediate pathogenic outcomes remains unclear. Here, we generate a soluble pyridine nucleotide transhydrogenase from Escherichia coli (EcSTH), which can elevate the NADH/NAD⁺ ratio and meantime reduce the NADPH/NADP⁺ ratio. Additionally, we fuse EcSTH with previously described LbNOX (a water-forming NADH oxidase from Lactobacillus brevis) to resume the NADH/NAD⁺ ratio. With these tools and by using genome-wide CRISPR/Cas9 library screens and metabolic profiling in mammalian cells, we find that accumulated NADH deregulates PRPS2 (Ribose-phosphate pyrophosphokinase 2)-mediated downstream purine biosynthesis t

SUBMITTER: Yang R 

PROVIDER: S-EPMC9672040 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature