NAD⁺ kinase

NAD+ kinase
Ribbon diagram of NAD+ kinase in complex with substrates.[1]
Identifiers
EC no.	2.7.1.23
CAS no.	9032-66-0
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
Search PMC articles PubMed articles NCBI proteins

NADK
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3PFN
Identifiers
Aliases	NADK, dJ283E3.1, NAD kinase
External IDs	OMIM: 611616; MGI: 2183149; HomoloGene: 49724; GeneCards: NADK; OMA:NADK - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[2] Band 1p36.33 Start 1,751,232 bp[2] End 1,780,457 bp[2]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[3] Band 4|4 E2 Start 155,646,835 bp[3] End 155,675,458 bp[3]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in blood granulocyte monocyte spleen right lobe of liver right adrenal gland right adrenal cortex left adrenal cortex mucosa of transverse colon gastric mucosa Top expressed in granulocyte pyloric antrum brown adipose tissue right kidney gastric mucosa tibiofemoral joint adrenal gland left lobe of liver mucous cell of stomach proximal tubule More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding NAD+ kinase activity protein binding ATP binding metal ion binding kinase activity Cellular component cytosol Biological process ATP metabolic process metabolism NADP biosynthetic process NAD metabolic process phosphorylation positive regulation of insulin secretion involved in cellular response to glucose stimulus Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 65220 192185 Ensembl ENSG00000008130 ENSMUSG00000029063 UniProt O95544 P58058 RefSeq (mRNA) NM_001198993 NM_001198994 NM_001198995 NM_023018 NM_001353641 NM_001353642 NM_001159637 NM_138671 NM_001355599 RefSeq (protein) NP_001185922 NP_001185923 NP_001185924 NP_075394 NP_001340570 NP_001340571 NP_001153109 NP_619612 NP_001342528 Location (UCSC) Chr 1: 1.75 – 1.78 Mb Chr 4: 155.65 – 155.68 Mb PubMed search [4] [5]
Wikidata
View/Edit Human View/Edit Mouse

NAD⁺ kinase (EC 2.7.1.23, NADK) is an enzyme that converts nicotinamide adenine dinucleotide (NAD⁺) into NADP⁺ through phosphorylating the NAD⁺ coenzyme.^[6] NADP⁺ is an essential coenzyme that is reduced to NADPH primarily by the pentose phosphate pathway to provide reducing power in biosynthetic processes such as fatty acid biosynthesis and nucleotide synthesis.^[7] The structure of the NADK from the archaean Archaeoglobus fulgidus has been determined.^[1]

In humans, the genes NADK^[8] and MNADK^[9] encode NAD⁺ kinases localized in cytosol^[8] and mitochondria,^[9] respectively. Similarly, yeast have both cytosolic and mitochondrial isoforms, and the yeast mitochondrial isoform accepts both NAD⁺ and NADH as substrates for phosphorylation.^[10][11]

The reaction catalyzed by NADK is

ATP + NAD⁺ ${\displaystyle \rightleftharpoons }$ ADP + NADP⁺

NADK phosphorylates NAD⁺ at the 2’ position of the ribose ring that carries the adenine moiety. It is highly selective for its substrates, NAD and ATP, and does not tolerate modifications either to the phosphoryl acceptor, NAD, or the pyridine moiety of the phosphoryl donor, ATP.^[8] NADK also uses metal ions to coordinate the ATP in the active site. In vitro studies with various divalent metal ions have shown that zinc and manganese are preferred over magnesium, while copper and nickel are not accepted by the enzyme at all.^[8] A proposed mechanism involves the 2' alcohol oxygen acting as a nucleophile to attack the gamma-phosphoryl of ATP, releasing ADP.

NADK is highly regulated by the redox state of the cell. Whereas NAD is predominantly found in its oxidized state NAD⁺, the phosphorylated NADP is largely present in its reduced form, as NADPH.^[12][13] Thus, NADK can modulate responses to oxidative stress by controlling NADP synthesis. Bacterial NADK is shown to be inhibited allosterically by both NADPH and NADH.^[14] NADK is also reportedly stimulated by calcium/calmodulin binding in certain cell types, such as neutrophils.^[15] NAD kinases in plants and sea urchin eggs have also been found to bind calmodulin.^[16][17]

Due to the essential role of NADPH in lipid and DNA biosynthesis and the hyperproliferative nature of most cancers, NADK is an attractive target for cancer therapy. Furthermore, NADPH is required for the antioxidant activities of thioredoxin reductase and glutaredoxin.^[18][19] Thionicotinamide and other nicotinamide analogs are potential inhibitors of NADK,^[20] and studies show that treatment of colon cancer cells with thionicotinamide suppresses the cytosolic NADPH pool to increase oxidative stress and synergizes with chemotherapy.^[21]

While the role of NADK in increasing the NADPH pool appears to offer protection against apoptosis, there are also cases where NADK activity appears to potentiate cell death. Genetic studies done in human haploid cell lines indicate that knocking out NADK may protect from certain non-apoptotic stimuli.^[22]

• Oxidative phosphorylation
• Electron transport chain
• Metabolism

• ENZYME entry on EC 2.7.1.23
• BRENDA entry on EC 2.7.1.23
• PDBe-KB provides an overview of all the structure information available in the PDB for Human NAD kinase