期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：5
页码：1386-1391
DOI：10.1073/pnas.1417290112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceMetabolism relies on a set of molecules that provide the chemical framework for all cellular activities. Among these molecules is NADP, a metabolite synthesized from vitamin B3 that is critical for basic metabolism, calcium signaling, and antiinflammatory processes. Despite NADP's fundamental importance, very little is known about how animal cells regulate their NADP pool. This study shows that the enzyme NAD kinase is required for maintaining NADP levels in animals, is essential for embryonic development, and exhibits conserved regulatory mechanisms among evolutionarily diverse animals such as humans and sea urchins. Together, these results reveal new insights into why vitamin B3 is essential and how it is converted to NADP, and suggests new therapeutic avenues to improve human and animal metabolism. Nicotinamide adenine dinucleotide phosphate (NADP) is a critical cofactor during metabolism, calcium signaling, and oxidative defense, yet how animals regulate their NADP pools in vivo and how NADP-synthesizing enzymes are regulated have long remained unknown. Here we show that expression of Nadk, an NAD+ kinase-encoding gene, governs NADP biosynthesis in vivo and is essential for development in Xenopus frog embryos. Unexpectedly, we found that embryonic Nadk expression is dynamic, showing cell type-specific up-regulation during both frog and sea urchin embryogenesis. We analyzed the NAD kinases (NADKs) of a variety of deuterostome animals, finding two conserved internal domains forming a catalytic core but a highly divergent N terminus. One type of N terminus (found in basal species such as the sea urchin) mediates direct catalytic activation of NADK by Ca2+/calmodulin (CaM), whereas the other (typical for vertebrates) is phosphorylated by a CaM kinase-dependent mechanism. This work indicates that animal NADKs govern NADP biosynthesis in vivo and are regulated by evolutionarily divergent and conserved CaM-dependent mechanisms.
