The metabolites NADP+ and NADPH are the targets of the circadian protein Nocturnin (Curled).

TitleThe metabolites NADP+ and NADPH are the targets of the circadian protein Nocturnin (Curled).
Publication TypeJournal Article
Year of Publication2019
AuthorsEstrella, MA, Du, J, Chen, L, Rath, S, Prangley, E, Chitrakar, A, Aoki, T, Schedl, P, Rabinowitz, J, Korennykh, A
JournalNat Commun
Volume10
Issue1
Pagination2367
Date Published2019 05 30
ISSN2041-1723
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.

DOI10.1038/s41467-019-10125-z
Alternate JournalNat Commun
PubMed ID31147539
PubMed Central IDPMC6542800
Grant ListR01 GM110161 / GM / NIGMS NIH HHS / United States
DP1 DK113643 / DK / NIDDK NIH HHS / United States
P30 CA072720 / CA / NCI NIH HHS / United States
SU2C-AACR-DT-20-16 / / Lustgarten Foundation (Lustgarten Foundation for Pancreatic Cancer Research) / International
T32 GM007388 / GM / NIGMS NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States
P41 GM111244 / GM / NIGMS NIH HHS / United States
1R01GM110161 / / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) / International
F99 CA212468 / CA / NCI NIH HHS / United States
R35 GM126975 / GM / NIGMS NIH HHS / United States