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Q13423 (NNTM_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 142. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
NAD(P) transhydrogenase, mitochondrial

EC=1.6.1.2
Alternative name(s):
Nicotinamide nucleotide transhydrogenase
Pyridine nucleotide transhydrogenase
Gene names
Name:NNT
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1086 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

The transhydrogenation between NADH and NADP is coupled to respiration and ATP hydrolysis and functions as a proton pump across the membrane. May play a role in reactive oxygen species (ROS) detoxification in the adrenal gland. Ref.7

Catalytic activity

NADPH + NAD+ = NADP+ + NADH.

Subunit structure

Homodimer By similarity.

Subcellular location

Mitochondrion inner membrane; Multi-pass membrane protein; Matrix side Potential.

Tissue specificity

Widely expressed with expression most readily detectable in adrenal, heart, kidney, thyroid and adipose tissues. Ref.7

Involvement in disease

Glucocorticoid deficiency 4 (GCCD4) [MIM:614736]: A rare, potentially lethal, autosomal recessive disorder characterized by resistance to ACTH action on the adrenal cortex, adrenal insufficiency and an inability of the adrenal cortex to produce cortisol. It usually presents in the neonatal period or in early childhood with episodes of hypoglycemia and other symptoms related to cortisol deficiency, including failure to thrive, recurrent illnesses or infections, convulsions, and shock. In a small number of patients hypoglycemia can be sufficiently severe and persistent that it leads to serious long-term neurological damage or death. The diagnosis is readily confirmed with a low plasma cortisol measurement in the presence of an elevated ACTH level, and normal aldosterone and plasma renin measurements.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.7

Sequence similarities

In the N-terminal section; belongs to the AlaDH/PNT family.

In the C-terminal section; belongs to the PNT beta subunit family.

Ontologies

Keywords
   Cellular componentMembrane
Mitochondrion
Mitochondrion inner membrane
   DiseaseDisease mutation
   DomainTransit peptide
Transmembrane
Transmembrane helix
   LigandNAD
NADP
   Molecular functionOxidoreductase
   PTMAcetylation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcellular metabolic process

Traceable author statement. Source: Reactome

hydrogen ion transmembrane transport

Traceable author statement Ref.1. Source: GOC

oxidation-reduction process

Traceable author statement Ref.8. Source: UniProtKB

proton transport

Traceable author statement Ref.8. Source: UniProtKB

reactive oxygen species metabolic process

Inferred from mutant phenotype Ref.7. Source: UniProtKB

small molecule metabolic process

Traceable author statement. Source: Reactome

tricarboxylic acid cycle

Traceable author statement Ref.8. Source: UniProtKB

   Cellular_componentintegral component of membrane

Inferred from electronic annotation. Source: UniProtKB-KW

mitochondrial inner membrane

Traceable author statement Ref.8. Source: UniProtKB

mitochondrial respiratory chain

Traceable author statement Ref.8. Source: UniProtKB

mitochondrion

Inferred from direct assay. Source: LIFEdb

   Molecular_functionNAD binding

Traceable author statement Ref.8. Source: UniProtKB

NAD(P)+ transhydrogenase (AB-specific) activity

Inferred from electronic annotation. Source: UniProtKB-EC

NAD(P)+ transhydrogenase (B-specific) activity

Traceable author statement Ref.1. Source: UniProtKB

NAD(P)+ transhydrogenase activity

Inferred from experiment. Source: Reactome

NADP binding

Inferred from direct assay Ref.8. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – 4343Mitochondrion By similarity
Chain44 – 10861043NAD(P) transhydrogenase, mitochondrial
PRO_0000001055

Regions

Topological domain44 – 474431Mitochondrial matrix
Transmembrane475 – 49319Helical; Potential
Transmembrane501 – 52121Helical; Potential
Transmembrane527 – 54620Helical; Potential
Transmembrane558 – 57821Helical; Potential
Topological domain579 – 59517Mitochondrial matrix
Transmembrane596 – 61621Helical; Potential
Transmembrane622 – 64221Helical; Potential
Transmembrane646 – 66621Helical; Potential
Transmembrane672 – 69120Helical; Potential
Transmembrane702 – 72221Helical; Potential
Topological domain723 – 73917Cytoplasmic
Transmembrane740 – 76021Helical; Potential
Transmembrane778 – 79720Helical; Potential
Transmembrane801 – 81919Helical; Potential
Transmembrane833 – 85321Helical; Potential
Transmembrane857 – 87923Helical; Potential
Topological domain880 – 1086207Mitochondrial matrix
Nucleotide binding229 – 25931NAD By similarity
Nucleotide binding965 – 9706NADP
Nucleotide binding1007 – 10115NADP
Nucleotide binding1042 – 10498NADP
Nucleotide binding1068 – 10692NADP

Sites

Binding site9331NADP; via amide nitrogen

Amino acid modifications

Modified residue701N6-acetyllysine Ref.5
Modified residue1171N6-succinyllysine By similarity
Modified residue2241N6-succinyllysine By similarity
Modified residue2941N6-succinyllysine By similarity
Modified residue3311N6-succinyllysine By similarity
Modified residue3971N6-acetyllysine Ref.5
Modified residue10791N6-succinyllysine By similarity

Natural variations

Natural variant1931S → N in GCCD4. Ref.7
VAR_068781
Natural variant3571T → A in GCCD4. Ref.7
VAR_068782
Natural variant3651H → P in GCCD4. Ref.7
VAR_068783
Natural variant4371P → L in GCCD4. Ref.7
VAR_068784
Natural variant5331A → V in GCCD4. Ref.7
VAR_068785
Natural variant6641G → R in GCCD4. Ref.7
VAR_068786
Natural variant6781G → R in GCCD4. Ref.7
VAR_068787
Natural variant8621G → D in GCCD4. Ref.7
VAR_068788
Natural variant9771L → P in GCCD4. Ref.7
VAR_068789
Natural variant10081A → P in GCCD4. Ref.7
VAR_068790
Natural variant10091N → K in GCCD4. Ref.7
VAR_068791

Experimental info

Sequence conflict1761A → T in CAA90428. Ref.2
Sequence conflict2121G → E in CAD38536. Ref.3
Sequence conflict2461A → E in AAC51914. Ref.1
Sequence conflict2621A → S in AAC51914. Ref.1
Sequence conflict7061F → S in AAC51914. Ref.1
Sequence conflict7311T → P in AAC51914. Ref.1
Sequence conflict8101S → A in CAA90428. Ref.2
Sequence conflict8241A → P in CAA90428. Ref.2
Sequence conflict8711I → P in AAC51914. Ref.1
Sequence conflict9291I → F in AAC51914. Ref.1
Sequence conflict10591K → R in CAD38536. Ref.3

Secondary structure

..................................... 1086
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q13423 [UniParc].

Last modified August 16, 2004. Version 3.
Checksum: 8A437658CA0EB41B

FASTA1,086113,896
        10         20         30         40         50         60 
MANLLKTVVT GCSCPLLSNL GSCKGLRVKK DFLRTFYTHQ ELWCKAPVKP GIPYKQLTVG 

        70         80         90        100        110        120 
VPKEIFQNEK RVALSPAGVQ NLVKQGFNVV VESGAGEASK FSDDHYRVAG AQIQGAKEVL 

       130        140        150        160        170        180 
ASDLVVKVRA PMVNPTLGVH EADLLKTSGT LISFIYPAQN PELLNKLSQR KTTVLAMDQV 

       190        200        210        220        230        240 
PRVTIAQGYD ALSSMANIAG YKAVVLAANH FGRFFTGQIT AAGKVPPAKI LIVGGGVAGL 

       250        260        270        280        290        300 
ASAGAAKSMG AIVRGFDTRA AALEQFKSLG AEPLEVDLKE SGEGQGGYAK EMSKEFIEAE 

       310        320        330        340        350        360 
MKLFAQQCKE VDILISTALI PGKKAPVLFN KEMIESMKEG SVVVDLAAEA GGNFETTKPG 

       370        380        390        400        410        420 
ELYIHKGITH IGYTDLPSRM ATQASTLYSN NITKLLKAIS PDKDNFYFDV KDDFDFGTMG 

       430        440        450        460        470        480 
HVIRGTVVMK DGKVIFPAPT PKNIPQGAPV KQKTVAELEA EKAATITPFR KTMSTASAYT 

       490        500        510        520        530        540 
AGLTGILGLG IAAPNLAFSQ MVTTFGLAGI VGYHTVWGVT PALHSPLMSV TNAISGLTAV 

       550        560        570        580        590        600 
GGLALMGGHL YPSTTSQGLA ALAAFISSVN IAGGFLVTQR MLDMFKRPTD PPEYNYLYLL 

       610        620        630        640        650        660 
PAGTFVGGYL AALYSGYNIE QIMYLGSGLC CVGALAGLST QGTARLGNAL GMIGVAGGLA 

       670        680        690        700        710        720 
ATLGVLKPGP ELLAQMSGAM ALGGTIGLTI AKRIQISDLP QLVAAFHSLV GLAAVLTCIA 

       730        740        750        760        770        780 
EYIIEYPHFA TDAAANLTKI VAYLGTYIGG VTFSGSLIAY GKLQGLLKSA PLLLPGRHLL 

       790        800        810        820        830        840 
NAGLLAASVG GIIPFMVDPS FTTGITCLGS VSALSAVMGV TLTAAIGGAD MPVVITVLNS 

       850        860        870        880        890        900 
YSGWALCAEG FLLNNNLLTI VGALIGSSGA ILSYIMCVAM NRSLANVILG GYGTTSTAGG 

       910        920        930        940        950        960 
KPMEISGTHT EINLDNAIDM IREANSIIIT PGYGLCAAKA QYPIADLVKM LTEQGKKVRF 

       970        980        990       1000       1010       1020 
GIHPVAGRMP GQLNVLLAEA GVPYDIVLEM DEINHDFPDT DLVLVIGAND TVNSAAQEDP 

      1030       1040       1050       1060       1070       1080 
NSIIAGMPVL EVWKSKQVIV MKRSLGVGYA AVDNPIFYKP NTAMLLGDAK KTCDALQAKV 


RESYQK 

« Hide

References

« Hide 'large scale' references
[1]"Cloning and deduced amino acid sequence of human nicotinamide nucleotide transhydrogenase."
Ware J., Zieger B.
DNA Seq. 7:369-374(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"The cDNA sequence of proton-pumping nicotinamide nucleotide transhydrogenase from man and mouse."
Lagberg E.M., Betsholtz C., Rydstrom J.
Biochim. Biophys. Acta 1273:203-205(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Heart.
[3]"The full-ORF clone resource of the German cDNA consortium."
Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I.
BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Skeletal muscle.
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]"Lysine acetylation targets protein complexes and co-regulates major cellular functions."
Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M.
Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-70 AND LYS-397, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[6]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[7]"Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency."
Meimaridou E., Kowalczyk J., Guasti L., Hughes C.R., Wagner F., Frommolt P., Nurnberg P., Mann N.P., Banerjee R., Saka H.N., Chapple J.P., King P.J., Clark A.J., Metherell L.A.
Nat. Genet. 44:740-742(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, TISSUE SPECIFICITY, VARIANTS GCCD4 ASN-193; ALA-357; PRO-365; LEU-437; VAL-533; ARG-664; ARG-678; ASP-862; PRO-977; PRO-1008 AND LYS-1009.
[8]"The high-resolution structure of the NADP(H)-binding component (dIII) of proton-translocating transhydrogenase from human heart mitochondria."
White S.A., Peake S.J., McSweeney S., Leonard G., Cotton N.P.J., Jackson J.B.
Structure 8:1-12(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 880-1086 IN COMPLEX WITH NADP.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U40490 mRNA. Translation: AAC51914.1.
Z50101 mRNA. Translation: CAA90428.1.
AL831822 mRNA. Translation: CAD38536.1.
BC110543 mRNA. Translation: AAI10544.1.
PIRG02257.
RefSeqNP_036475.3. NM_012343.3.
NP_892022.2. NM_182977.2.
XP_005248331.1. XM_005248274.2.
UniGeneHs.482043.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1DJLX-ray2.00A/B880-1086[»]
1PT9X-ray2.42A/B880-1086[»]
1U31X-ray2.20A/B880-1086[»]
ProteinModelPortalQ13423.
SMRQ13423. Positions 902-1083.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid117076. 21 interactions.
IntActQ13423. 2 interactions.
MINTMINT-3027647.
STRING9606.ENSP00000264663.

Chemistry

DrugBankDB00157. NADH.

PTM databases

PhosphoSiteQ13423.

Polymorphism databases

DMDM51338801.

Proteomic databases

PaxDbQ13423.
PeptideAtlasQ13423.
PRIDEQ13423.

Protocols and materials databases

DNASU23530.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000264663; ENSP00000264663; ENSG00000112992.
ENST00000344920; ENSP00000343873; ENSG00000112992.
GeneID23530.
KEGGhsa:23530.
UCSCuc003joe.3. human.

Organism-specific databases

CTD23530.
GeneCardsGC05P043638.
H-InvDBHIX0032203.
HGNCHGNC:7863. NNT.
HPACAB004975.
HPA004829.
MIM607878. gene.
614736. phenotype.
neXtProtNX_Q13423.
Orphanet361. Familial glucocorticoid deficiency.
PharmGKBPA31667.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG1282.
HOGENOMHOG000160623.
HOVERGENHBG006511.
InParanoidQ13423.
KOK00323.
OMAKPGIPYK.
OrthoDBEOG722J7T.
PhylomeDBQ13423.
TreeFamTF300636.

Enzyme and pathway databases

ReactomeREACT_111217. Metabolism.

Gene expression databases

ArrayExpressQ13423.
BgeeQ13423.
CleanExHS_NNT.
GenevestigatorQ13423.

Family and domain databases

InterProIPR008142. Ala_DH/PNT_CS1.
IPR008143. Ala_DH/PNT_CS2.
IPR007886. AlaDH/PNT_N.
IPR007698. AlaDH/PNT_NAD(H)-bd.
IPR012136. NADH_DH_b.
IPR026255. NADP_transhyd_a.
IPR024605. NADP_transhyd_a_C.
[Graphical view]
PfamPF01262. AlaDh_PNT_C. 1 hit.
PF05222. AlaDh_PNT_N. 1 hit.
PF12769. DUF3814. 1 hit.
PF02233. PNTB. 1 hit.
[Graphical view]
SMARTSM01002. AlaDh_PNT_C. 1 hit.
SM01003. AlaDh_PNT_N. 1 hit.
[Graphical view]
TIGRFAMsTIGR00561. pntA. 1 hit.
PROSITEPS00836. ALADH_PNT_1. 1 hit.
PS00837. ALADH_PNT_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ13423.
GeneWikiNNT_(gene).
GenomeRNAi23530.
NextBio46004.
PROQ13423.
SOURCESearch...

Entry information

Entry nameNNTM_HUMAN
AccessionPrimary (citable) accession number: Q13423
Secondary accession number(s): Q16796, Q2TB60, Q8N3V4
Entry history
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: August 16, 2004
Last modified: April 16, 2014
This is version 142 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 5

Human chromosome 5: entries, gene names and cross-references to MIM