NADP+ synthesis (NAD kinases NADK/NADK2) and nicotinamide riboside salvage (NMRK1/NMRK2)

Two committed reactions that complete the cellular NAD(P) cofactor network beyond the core NAD+ biosynthesis hub. First, the nicotinamide riboside (NR) salvage entry: nicotinamide riboside kinases NMRK1 (ubiquitous) and NMRK2 (muscle-enriched) phosphorylate the dietary/circulating NAD+ precursor nicotinamide riboside (and nicotinic acid riboside, and the reduced vitamers) with ATP to nicotinamide mononucleotide (NMN) / nicotinic acid mononucleotide (NaMN). NMN then enters the NMNAT step of the NAD+ biosynthesis hub (see MODULE:nad_biosynthesis_salvage), making NR the shortest two-step route to NAD+ and the basis for NR/NMN nutraceutical supplementation. Second, the NADP+ branch: NAD kinases phosphorylate the 2'-hydroxyl of the adenine ribose of NAD+ with ATP to give NADP+, the sole de novo source of the NADP(H) pool that drives reductive biosynthesis and antioxidant defence (glutathione and thioredoxin regeneration). Humans have two compartment-specific NAD kinases from distinct families: cytosolic NADK supplies the cytosolic/nuclear NADP(H) pool, and mitochondrial NADK2 supplies the matrix NADP(H) pool required for proline biosynthesis (feeding NADPH to ALDH18A1/P5CS), mitochondrial one-carbon metabolism and fatty-acid oxidation. NADK2 deficiency causes a severe metabolic encephalopathy (hyperlysinemia, 2,4-dienoyl-CoA reductase deficiency); NADK activity is itself redox- and growth-signal-regulated.

MODULE:nadp_synthesis_and_nr_salvageDRAFTMetabolic Pathwaymodules/nadp_synthesis_and_nr_salvage.yaml
NADP+ biosynthetic processGO:0006741 NAD+ biosynthetic process via the salvage pathwayGO:0034355
GO:0006741
NADP+ biosynthetic process
NADK and NADK2 carry out NADP+ biosynthesis (GO:0006741) by phosphorylating NAD+.
GO:0034355
NAD+ biosynthetic process via the salvage pathway
NMRK1/NMRK2 provide the nicotinamide-riboside salvage entry into NAD+ biosynthesis (GO:0034355).
file:human/NADK/NADK-ai-review.yaml
NADK gene review (human)
The cytosolic NAD+->NADP+ step (UniProtKB:O95544, GO:0003951) matches the completed human NADK review.
file:human/NADK2/NADK2-ai-review.yaml
NADK2 gene review (human)
The mitochondrial NAD+->NADP+ step (UniProtKB:Q4G0N4, GO:0003951) matches the completed human NADK2 review.
file:human/NMRK1/NMRK1-ai-review.yaml
NMRK1 gene review (human)
The NR->NMN salvage step (UniProtKB:Q9NWW6, GO:0050262) matches the completed human NMRK1 review.
file:human/NMRK2/NMRK2-ai-review.yaml
NMRK2 gene review (human)
The muscle NR->NMN salvage step (UniProtKB:Q9NPI5, GO:0050262) matches the completed human NMRK2 review.
4Nodes
3Parts
0Variant Sets
0Variants
3Annotons
1Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:nadp_synthesis_and_nr_salvage deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

4 gene-function check(s) reflected in core functions · 0 conflict(s) · 3 evidence or coverage gap(s) (7 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
nmrk_activity NMRK1 (human)
UniProtKB:Q9NWW6
Family Representative 		ribosylnicotinamide kinase activity
GO:0050262 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nmrk_activity NMRK2 (human)
UniProtKB:Q9NPI5
Family Representative 		ribosylnicotinamide kinase activity
GO:0050262 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nadk_activity NADK (human)
UniProtKB:O95544
Family Representative 		NAD+ kinase activity
GO:0003951 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nadk2_activity NADK2 (human)
UniProtKB:Q4G0N4
Family Representative 		NAD+ kinase activity
GO:0003951 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nmrk_activity NMRK / nicotinamide riboside kinase (uridine-kinase / NRK) family
PANTHER:PTHR10285
Family 		ribosylnicotinamide kinase activity
GO:0050262 		Family Scope Restricted
GO:0050262 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. NRK subfamilies only, as nad_de_novo_and_salvage_fungal and nadp_synthesis_and_nr_salvage assert. Both modules select the base family.
nadk_activity NADK / cytosolic NAD kinase family
PANTHER:PTHR20275
Family 		NAD+ kinase activity
GO:0003951 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR20275.
nadk2_activity NADK2 / mitochondrial NAD kinase family
PANTHER:PTHR13158
Family 		NAD+ kinase activity
GO:0003951 		Family Function Unreviewed
Family review leaves GO:0003951 UNRESOLVED. Safe for the eukaryotic clade under PTN000994636: human NADK2 has direct activity, mouse Nadk2 loss lowers mitochondrial NADP(H), and the other eukaryotic members, including nematode SF4 nadk-1, keep the GGDGT block. Not established for the bacterial members (about a third of UniProtKB members, assigned mostly to SF5 by HMM): only 1% match the Pfam NAD_kinase domain, against 72% of metazoan SF5 members, and most substitute the second glycine of the GGDG block while keeping the catalytic Asp. Many are named "Inorganic polyphosphate/ATP-NAD kinase" by UniProt and may be active; none has been assayed. Because the bacterial members sit inside SF5 (and a smaller set, 31 entries, is HMM-assigned to SF4), no subfamily-level scope expresses this; the boundary is the eukaryotic node. UNRESOLVED here means decided for the eukaryotic clade but not expressible as a subfamily scope.

Gene-review completeness (4/4 grounded genes reviewed)

4 complete review(s) · 0 with deep research · 0 missing review · 4 reviewed but lacking deep research

Gene Review Complete Deep research
NADK O95544 ✓ ✓ ✗
NADK2 Q4G0N4 ✓ ✓ ✗
NMRK1 Q9NWW6 ✓ ✓ ✗
NMRK2 Q9NPI5 ✓ ✓ ✗

Details

Context
cytosolGO:0005829 mitochondrial matrixGO:0005759
NADP+ synthesis (NAD kinases) and nicotinamide riboside salvageMetabolic Pathwaynadp_synthesis_and_nr_salvage
NADP+ biosynthetic processGO:0006741 NAD+ biosynthetic process via the salvage pathwayGO:0034355
Context
cytosolGO:0005829 mitochondrial matrixGO:0005759

NADP+ synthesis and nicotinamide-riboside salvage (GO:0006741 / GO:0034355), grounded to the completed human gene reviews. Two NAD kinases from DISTINCT PANTHER families phosphorylate NAD+ to NADP+ in separate compartments: cytosolic NADK (O95544, PTHR20275, GO:0003951; homotetramer, sole de novo cytosolic/nuclear NADP source, does not make NAADP) and mitochondrial NADK2 (Q4G0N4, PTHR13158, GO:0003951; supplies matrix NADP(H) for proline synthesis and FAO — deficiency causes DECRD / hyperlysinemia). The nicotinamide-riboside kinases NMRK1 (Q9NWW6) and NMRK2 (Q9NPI5) share one family (PTHR10285) and one activity (GO:0050262 ribosylnicotinamide kinase + GO:0061769 nicotinate riboside kinase), phosphorylating NR to NMN as the shortest salvage entry to NAD+; NMRK2 is muscle-enriched and additionally a genuine integrin-binding protein (ITGB1BP3/MIBP, GO:0005178). NR salvage feeds NMN into the NMNAT step of the sibling module MODULE:nad_biosynthesis_salvage (node nmnat_hub); the resulting NAD+ pool is the substrate for the NAD kinases here, so this module extends the NAD+ hub to cover the NADP branch and the NR entry point. GO term ids/labels verified against the local go.db. All four genes are cofactor-metabolism enzymes without EC/localization over-annotation concerns (see per-gene reviews for annotation-level actions).

Connections

nr_to_nmn -> nad_to_nadp_cytosolic Provides Input For
The NMN made by NMRK1/NMRK2 is adenylylated to NAD+ by the NMNAT step of the NAD+ biosynthesis hub (node nmnat_hub in MODULE:nad_biosynthesis_salvage); that NAD+ pool is in turn the substrate for the NAD kinases, linking NR salvage (input) to NADP+ synthesis (output).
Part 1: nicotinamide riboside salvage to NMN
Nicotinamide riboside kinases (NMRK1/NMRK2)Reactionnr_to_nmn

Annotons

NMRK1/NMRK2: nicotinamide riboside kinase
nmrk_activity
Participant: Family: NMRK / nicotinamide riboside kinase (uridine-kinase / NRK) family
Family:
NMRK / nicotinamide riboside kinase (uridine-kinase / NRK) familyPANTHER:PTHR10285
Representative Members: NMRK1 (human)UniProtKB:Q9NWW6 NMRK2 (human)UniProtKB:Q9NPI5

Function

ribosylnicotinamide kinase activityGO:0050262
Substrates: nicotinamide riboside (NR) ATP (with Mg2+)
Products: nicotinamide mononucleotide (NMN) ADP

Locations

cytosolGO:0005829

Phosphorylates nicotinamide riboside to NMN (shortest salvage route to NAD+).

Part 2: cytosolic NAD+ phosphorylation to NADP+
Cytosolic NAD kinase (NADK)Reactionnad_to_nadp_cytosolic

Annotons

NADK: cytosolic NAD+ kinase
nadk_activity
Participant: Family: NADK / cytosolic NAD kinase family
Family:
NADK / cytosolic NAD kinase familyPANTHER:PTHR20275
Representative Members: NADK (human)UniProtKB:O95544

Function

NAD+ kinase activityGO:0003951
Substrates: NAD+ ATP (with divalent metal)
Products: NADP+ ADP

Locations

cytosolGO:0005829

Phosphorylates NAD+ to NADP+ in the cytosol/nucleus.

Part 3: mitochondrial NAD+ phosphorylation to NADP+
Mitochondrial NAD kinase (NADK2)Reactionnad_to_nadp_mitochondrial

Annotons

NADK2: mitochondrial NAD+ kinase
nadk2_activity
Participant: Family: NADK2 / mitochondrial NAD kinase family
Family:
NADK2 / mitochondrial NAD kinase familyPANTHER:PTHR13158
Representative Members: NADK2 (human)UniProtKB:Q4G0N4

Function

NAD+ kinase activityGO:0003951
Substrates: NAD+ ATP (with divalent metal)
Products: NADP+ ADP

Locations

mitochondrial matrixGO:0005759

Phosphorylates NAD+ to NADP+ in the mitochondrial matrix.