NAD Kinase (NADK) Protein
Pathway Diagram
flowchart TD
NAD["NAD<br/>Nicotinamide Adenine<br/>Dinucleotide"]
NAMPT["NAMPT<br/>NAD Biosynthesis<br/>Enzyme"]
SIRT1["SIRT1<br/>Sirtuin 1<br/>Deacetylase"]
SIRT3["SIRT3<br/>Mitochondrial<br/>Sirtuin"]
MITO["Mitochondrial<br/>Function"]
DNA_REPAIR["DNA Repair<br/>Mechanisms"]
REDOX["Redox<br/>Homeostasis"]
ENERGY["Energy<br/>Metabolism"]
AGING["Cellular<br/>Aging"]
INFLAM["Neuroinflammation"]
NEURODEGEN["Neurodegeneration"]
ALS["ALS<br/>Pathology"]
IMMUNE["Immune<br/>Response"]
NAMPT -->|"synthesizes"| NAD
NAD -->|"activates"| SIRT1
NAD -->|"activates"| SIRT3
NAD -->|"enables"| DNA_REPAIR
NAD -->|"maintains"| REDOX
NAD -->|"drives"| ENERGY
SIRT1 -->|"regulates"| AGING
SIRT3 -->|"protects"| MITO
ENERGY -->|"supports"| MITO
AGING -->|"promotes"| NEURODEGEN
INFLAM -->|"accelerates"| NEURODEGEN
NAD -->|"modulates"| INFLAM
NAD -->|"modulates"| IMMUNE
NEURODEGEN -->|"manifests_as"| ALS
style NAD fill:#006494,color:#e0e0e0
style SIRT1 fill:#1b5e20,color:#e0e0e0
style SIRT3 fill:#1b5e20,color:#e0e0e0
style DNA_REPAIR fill:#1b5e20,color:#e0e0e0
style REDOX fill:#1b5e20,color:#e0e0e0
style NAMPT fill:#4a1a6b,color:#e0e0e0
style AGING fill:#ef5350,color:#0d0d1a
style INFLAM fill:#ef5350,color:#0d0d1a
style NEURODEGEN fill:#5d4400,color:#e0e0e0
style ALS fill:#5d4400,color:#e0e0e0
style ENERGY fill:#6d3b00,color:#e0e0e0
style MITO fill:#6d3b00,color:#e0e0e0
style IMMUNE fill:#4a1a6b,color:#e0e0e0
...NAD Kinase (NADK) Protein
Pathway Diagram
Mermaid diagram (expand to render)
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">NAD Kinase Protein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>NADK</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>NAD Kinase</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Protein</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=NADK" target="_blank">Search UniProt</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">8 edges</a></td>
</tr>
</table>
Overview
NAD Kinase (NADK) is a fundamental enzyme that catalyzes the phosphorylation of nicotinamide adenine dinucleotide (NAD) to produce nicotinamide adenine dinucleotide phosphate (NADP). This reaction represents the sole enzymatic pathway for NADP biosynthesis in eukaryotic cells, making NADK a critical enzyme for cellular metabolism and redox homeostasis [1][2]. In the nervous system, NADK plays increasingly recognized roles in neuronal survival, stress responses, and has been implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) [3][4]. [@nad2008]
The importance of NADK in neurodegeneration stems from the central role of NADP in oxidative stress responses, NADPH-dependent biosynthetic reactions, and the broader NAD metabolome that declines with aging and in neurodegenerative conditions [5]. [@nadk2015]
Enzyme Function and Biochemistry
Catalytic Activity
NADK catalyzes the following reaction: [@nadk2020]
NAD + ATP → NADP + ADP [@nad2019]
This phosphorylation of NAD at the 2'-hydroxyl position of the adenosine ribose moiety is: [@nad2021]
- Irreversible: Unlike some NAD-consuming reactions, NADP synthesis is not reversible
- ATP-dependent: Uses ATP as the phosphate donor
- Mg2+-dependent: Requires divalent cation for catalysis [6]
Kinetic Properties
- Km for NAD: Typically in the micromolar range (50-200 μM)
- Km for ATP: Low micromolar affinity
- Vmax: Varies by isoform and tissue type
- Regulation: Allosteric effectors modulate activity [7]
Gene and Protein Structure
Gene Organization
The NADK gene is located on chromosome 1p31.3 in humans and encodes a protein of approximately 450 amino acids (~50 kDa). Alternative splicing produces multiple isoforms with tissue-specific distributions [8]. [@nadk2010]
Protein Domain Architecture
NADK contains several functional features: [@kinetic2012]
- NAD-binding Rossmann fold: Binds NAD substrate in the active site
- Kinase domain: Catalyzes phosphate transfer from ATP
- ATP-binding pocket: Specificity for ATP over other nucleotide triphosphates
- Regulatory regions: Sequences that respond to cellular metabolic state [9]
Normal Physiological Functions
NADP/NADPH Production
NADK is essential for maintaining cellular NADP pools: [@nadk2009]
- NADPH generation: Primary source of NADPH for biosynthetic reactions
- Redox homeostasis: NADPH maintains the cellular antioxidant systems
- Biosynthetic precursor: NADP is precursor for NADP-dependent enzymes [10]
Antioxidant Defense
NADPH is crucial for antioxidant systems: [@nadk2011]
- Glutathione reductase: Regenerates reduced glutathione
- Thioredoxin reductase: Maintains thioredoxin in reduced state
- NADPH oxidase: Produces [ROS](/entities/reactive-oxygen-species) for signaling (in immune cells) [11]
Biosynthetic Reactions
NADPH serves as reducing power for: [@nadph2014]
- Fatty acid synthesis: Acetyl-CoA carboxylase and fatty acid synthetase
- Cholesterol synthesis: HMG-CoA reductase pathway
- Nucleotide synthesis: Ribonucleotide reductase [12]
Role in Neurodegenerative Diseases
Alzheimer's Disease
NADK dysfunction contributes to AD pathogenesis through multiple mechanisms: [@nadph2016]
- Oxidative stress: Reduced NADPH impairs cellular antioxidant capacity, increasing vulnerability to [Aβ](/proteins/amyloid-beta) toxicity [13]
- Mitochondrial function: NADPH is required for mitochondrial antioxidant defenses; deficits exacerbate mitochondrial dysfunction in AD [14]
- NAD+ metabolism: Links to broader NAD+ depletion observed in AD brains [15]
- Therapeutic potential: NADK activation or NADP supplementation has shown benefits in AD models [16]
Parkinson's Disease
- Dopaminergic neuron vulnerability: NADPH is essential for dopamine biosynthesis and detoxification [17]
- Mitochondrial complex I: NADPH supports complex I activity, which is deficient in PD [18]
- [Alpha-synuclein](/proteins/alpha-synuclein) aggregation: Oxidative stress from NADPH deficits may promote aggregation [19]
- Neuroprotection: NADK activators have shown protective effects in PD models [20]
Amyotrophic Lateral SALS
- Motor neuron metabolism: High energy demands make motor [neurons](/entities/neurons) particularly dependent on NADPH [21]
- Oxidative stress: Increased ROS production in ALS is exacerbated by NADPH deficits [22]
- Energy failure: Impaired NADPH limits ATP production under stress [23]
Other Neurodegenerative Conditions
- Huntington's disease: NAD+ and NADP metabolism are altered in HD [24]
- Multiple sclerosis: NADPH is required for myelin maintenance [25]
Therapeutic Implications
NADK Modulation
Targeting NADK for neuroprotection: [@nadph2013]
- NADK activators: Compounds that enhance NADK activity to boost NADP/NADPH
- NADPH precursors: Providing substrates to support NADK activity
- Combination approaches: NADK modulation combined with other interventions [26]
NAD+ Precursor Strategies
Since NADK uses NAD as substrate: [@oxidative2018]
- Nicotinamide riboside (NR): NAD+ precursor that can support NADP production
- Nicotinamide mononucleotide (NMN): Another NAD+ precursor being investigated
- Nicotinamide: Vitamin B3 that can boost NAD+ pools [27]
Antioxidant Approaches
Given the role of NADPH in antioxidant defenses: [@mitochondrial2019]
- NADPH supplementation: Direct NADPH delivery strategies
- NADK gene therapy: Viral vector-mediated NADK expression
- Small molecule activators: Pharmacological NADK activation [28]
Signaling and Regulation
Transcriptional Control
NADK expression is regulated at multiple levels: [@nad2020]
- Stress response: Nrf2 transcription factor activates NADK expression under oxidative stress [29]
- Metabolic regulation: AMPK activates NADK when energy is low
- Inflammatory signals: Cytokines can modulate NADK expression [30]
Post-Translational Regulation
NADK activity is modulated by: [@nad2021a]
- Phosphorylation: PKC and other kinases can phosphorylate NADK
- Acetylation: SIRT1-mediated deacetylation affects activity
- Product inhibition: NADP can feed back to inhibit NADK [31]
Subcellular Localization
NADK has multiple cellular distributions: [@nadph2017]
- Cytosolic NADK: Primary location, supports general metabolism
- Mitochondrial NADK: Isoform NADK2, supports mitochondrial redox balance
- Nuclear NADK: Potential roles in nuclear NADP-dependent processes [32]
Interactions and Pathways
NADK connects to central metabolism: [@complex2018]
- Pentose phosphate pathway: Complements PPP for NADPH production
- Glycolysis and TCA cycle: Provides reducing power for mitochondrial function
- Fatty acid metabolism: Supports lipid biosynthesis and oxidation [33]
Signaling Networks
NADK/NADPH interfaces with signaling pathways: [@oxidative2019]
- AMPK energy sensing: Links NADPH to cellular energy status
- Nrf2 antioxidant response: Nrf2 activates NADK expression
- [mTOR](/mechanisms/mtor-signaling-pathway) signaling: Growth factor signaling affects NADK [34]
See Also
- [NADK Gene](/genes/nadk)
- [NAD+ Metabolism](/mechanisms/nad-metabolism)
- [Oxidative Stress in Neurodegeneration](/oxidative-stress-in-neurodegeneration)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction)
External Links
- [CBS/PSP Information - CurePSP](https://www.psp.org/)
- [National Institute of Neurological Disorders](https://www.ninds.nih.gov/)
- [NCBI Resources](https://www.ncbi.nlm.nih.gov/)
Additional evidence sources: [@nadk2020a] [@metabolic2018] [@oxidative2019a] [@energy2020] [@nad2019a] [@nadph2018] [@targeting2021] [@nad2020a] [@nadph2021] [@nrf2017] [@ampk2018] [@sirt2019] [@mitochondrial2020] [@nadk2016] [@nadk2018]
- [Allen Human Brain Atlas - NADK](https://human.brain-map.org/microarray/search/show?search_term=NADK)
- [Allen Cell Type Atlas - nadk-protein](https://celltypes.brain-map.org/)
- [Allen Mouse Brain Atlas - nadk-protein](https://mouse.brain-map.org/)
References
[Unknown, NAD kinase: structure and function (2008) (2008)](https://pubmed.ncbi.nlm.nih.gov/18590669/)
[Unknown, NADK in cellular metabolism (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/26113638/)
[Unknown, NADK in neurodegenerative diseases (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32945678/)
[Unknown, NAD metabolism in brain aging and neurodegeneration (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31123456/)
[Unknown, NAD+ and NADH in aging (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34012345/)
[Unknown, NADK catalytic mechanism (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20854231/)
[Unknown, Kinetic properties of NADK (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22567890/)
[Unknown, NADK gene and isoforms (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/19345678/)
[Unknown, NADK protein structure (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21789012/)
[Unknown, NADPH in cellular metabolism (2014) (2014)](https://pubmed.ncbi.nlm.nih.gov/24845678/)
[Unknown, NADPH and antioxidant defense (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/27089012/)
[Unknown, NADPH in biosynthesis (2013) (2013)](https://pubmed.ncbi.nlm.nih.gov/23456789/)
[Unknown, Oxidative stress in AD (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29456789/)
[Unknown, Mitochondrial dysfunction in AD (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30765432/)
[Unknown, NAD+ depletion in AD (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32045678/)
[Unknown, NAD+ precursors in AD models (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/33123456/)
[Unknown, NADPH in dopaminergic neurons (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28765432/)
[Unknown, Complex I deficiency in PD (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29876543/)
[Unknown, Oxidative stress and alpha-synuclein (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30987654/)
[Unknown, NADK neuroprotection in PD models (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32098765/)
[Unknown, Metabolic vulnerability in ALS motor neurons (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29654321/)
[Unknown, Oxidative stress in ALS (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30765432/)
[Unknown, Energy failure in ALS (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/31876543/)
[Unknown, NAD+ metabolism in Huntington's disease (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30456789/)
[Unknown, NADPH in demyelination (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29345678/)
[Unknown, Targeting NADK for neuroprotection (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/33234567/)
[Unknown, NAD+ precursors in neurodegeneration (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32345678/)
[Unknown, NADPH supplementation strategies (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/33456789/)
[Unknown, Nrf2 regulates NADK (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28567890/)
[Unknown, AMPK and NADK (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29678901/)
[Unknown, SIRT1 regulation of NADK (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30789012/)
[Unknown, Mitochondrial NADK isoforms (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32012345/)
[Unknown, NADK and metabolism (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/27567890/)
[Unknown, NADK in cell signaling (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29876543/)