The metabolites NADP and NADPH are the targets of the circadian protein Nocturnin (Curled). Author Michael Estrella, Jin Du, Li Chen, Sneha Rath, Eliza Prangley, Alisha Chitrakar, Tsutomu Aoki, Paul Schedl, Joshua Rabinowitz, Alexei Korennykh Publication Year 2019 Type Journal Article Abstract Nocturnin (NOCT) is a rhythmically expressed protein that regulates metabolism under the control of circadian clock. It has been proposed that NOCT deadenylates and regulates metabolic enzyme mRNAs. However, in contrast to other deadenylases, purified NOCT lacks the deadenylase activity. To identify the substrate of NOCT, we conducted a mass spectrometry screen and report that NOCT specifically and directly converts the dinucleotide NADP into NAD and NADPH into NADH. Further, we demonstrate that the Drosophila NOCT ortholog, Curled, has the same enzymatic activity. We obtained the 2.7 Å crystal structure of the human NOCT•NADPH complex, which revealed that NOCT recognizes the chemically unique ribose-phosphate backbone of the metabolite, placing the 2'-terminal phosphate productively for removal. We provide evidence for NOCT targeting to mitochondria and propose that NADP(H) regulation, which takes place at least in part in mitochondria, establishes the molecular link between circadian clock and metabolism. Journal Nat Commun Volume 10 Issue 1 Pages 2367 Date Published 05/2019 ISSN Number 2041-1723 DOI 10.1038/s41467-019-10125-z Alternate Journal Nat Commun PMCID PMC6542800 PMID 31147539 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML