Q13423 (NNTM_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
NAD(P) transhydrogenase, mitochondrial
EC=1.6.1.2

Alternative name(s):
Nicotinamide nucleotide transhydrogenase
Pyridine nucleotide transhydrogenase

Gene names

Name:

NNT

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1086 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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 component	Membrane Mitochondrion Mitochondrion inner membrane
Disease	Disease mutation
Domain	Transit peptide Transmembrane Transmembrane helix
Ligand	NAD NADP
Molecular function	Oxidoreductase
PTM	Acetylation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	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_component	integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW mitochondrial respiratory chain Traceable author statement Ref.8. Source: UniProtKB
Molecular_function	NAD binding Traceable author statement Ref.8. Source: UniProtKB NAD(P)+ transhydrogenase (AB-specific) activity Inferred from electronic annotation. Source: EC NAD(P)+ transhydrogenase (B-specific) activity Traceable author statement Ref.1. Source: UniProtKB NADP binding Inferred from direct assay Ref.8. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 43

43

Mitochondrion By similarity

Chain

44 – 1086

1043

NAD(P) transhydrogenase, mitochondrial

PRO_0000001055

Regions

Topological domain

44 – 474

431

Mitochondrial matrix

Transmembrane

475 – 493

19

Helical; Potential

Transmembrane

501 – 521

21

Helical; Potential

Transmembrane

527 – 546

20

Helical; Potential

Transmembrane

558 – 578

21

Helical; Potential

Topological domain

579 – 595

17

Mitochondrial matrix

Transmembrane

596 – 616

21

Helical; Potential

Transmembrane

622 – 642

21

Helical; Potential

Transmembrane

646 – 666

21

Helical; Potential

Transmembrane

672 – 691

20

Helical; Potential

Transmembrane

702 – 722

21

Helical; Potential

Topological domain

723 – 739

17

Cytoplasmic

Transmembrane

740 – 760

21

Helical; Potential

Transmembrane

778 – 797

20

Helical; Potential

Transmembrane

801 – 819

19

Helical; Potential

Transmembrane

833 – 853

21

Helical; Potential

Transmembrane

857 – 879

23

Helical; Potential

Topological domain

880 – 1086

207

Mitochondrial matrix

Nucleotide binding

229 – 259

31

NAD By similarity

Nucleotide binding

965 – 970

6

NADP

Nucleotide binding

1007 – 1011

5

NADP

Nucleotide binding

1042 – 1049

8

NADP

Nucleotide binding

1068 – 1069

2

NADP

Sites

Binding site

933

1

NADP; via amide nitrogen

Amino acid modifications

Modified residue

70

1

N6-acetyllysine Ref.5

Modified residue

397

1

N6-acetyllysine Ref.5

Natural variations

Natural variant

193

1

S → N in GCCD4. Ref.7

VAR_068781

Natural variant

357

1

T → A in GCCD4. Ref.7

VAR_068782

Natural variant

365

1

H → P in GCCD4. Ref.7

VAR_068783

Natural variant

437

1

P → L in GCCD4. Ref.7

VAR_068784

Natural variant

533

1

A → V in GCCD4. Ref.7

VAR_068785

Natural variant

664

1

G → R in GCCD4. Ref.7

VAR_068786

Natural variant

678

1

G → R in GCCD4. Ref.7

VAR_068787

Natural variant

862

1

G → D in GCCD4. Ref.7

VAR_068788

Natural variant

977

1

L → P in GCCD4. Ref.7

VAR_068789

Natural variant

1008

1

A → P in GCCD4. Ref.7

VAR_068790

Natural variant

1009

1

N → K in GCCD4. Ref.7

VAR_068791

Experimental info

Sequence conflict

176

1

A → T in CAA90428. Ref.2

Sequence conflict

212

1

G → E in CAD38536. Ref.3

Sequence conflict

246

1

A → E in AAC51914. Ref.1

Sequence conflict

262

1

A → S in AAC51914. Ref.1

Sequence conflict

706

1

F → S in AAC51914. Ref.1

Sequence conflict

731

1

T → P in AAC51914. Ref.1

Sequence conflict

810

1

S → A in CAA90428. Ref.2

Sequence conflict

824

1

A → P in CAA90428. Ref.2

Sequence conflict

871

1

I → P in AAC51914. Ref.1

Sequence conflict

929

1

I → F in AAC51914. Ref.1

Sequence conflict

1059

1

K → R in CAD38536. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

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.

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.

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.

.

.

1086

Helix Strand Turn

Details...

Helix

914 – 923

10

Beta strand

925 – 931

7

Helix

933 – 938

6

Helix

941 – 953

13

Beta strand

957 – 962

6

Beta strand

967 – 969

3

Helix

972 – 979

8

Helix

984 – 986

3

Beta strand

987 – 989

3

Helix

990 – 993

4

Helix

994 – 999

6

Beta strand

1001 – 1007

7

Helix

1010 – 1012

3

Helix

1015 – 1018

4

Turn

1023 – 1026

4

Helix

1032 – 1034

3

Beta strand

1035 – 1045

11

Helix

1055 – 1058

4

Beta strand

1062 – 1067

6

Helix

1069 – 1081

13

Sequences

	Sequence		Length	Mass (Da)
	Q13423 [UniParc]. Last modified August 16, 2004. Version 3. Checksum: 8A437658CA0EB41B	FASTA	1,086	113,896
	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

References

	« Hide 'large scale' referencesShow '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, MASS SPECTROMETRY.
[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.

IPI

IPI00337541.

PIR

G02257.

RefSeq

NP_036475.3. NM_012343.3.
NP_892022.2. NM_182977.2.

UniGene

Hs.482043.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1DJL	X-ray	2.00	A/B	880-1086	[»]
1PT9	X-ray	2.42	A/B	880-1086	[»]
1U31	X-ray	2.20	A/B	880-1086	[»]

ProteinModelPortal

Q13423.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q13423. 2 interactions.

MINT

MINT-3027647.

STRING

9606.ENSP00000264663.

PTM databases

PhosphoSite

Q13423.

Polymorphism databases

DMDM

51338801.

Proteomic databases

PaxDb

Q13423.

PeptideAtlas

Q13423.

PRIDE

Q13423.

Protocols and materials databases

DNASU

23530.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000264663; ENSP00000264663; ENSG00000112992.
ENST00000344920; ENSP00000343873; ENSG00000112992.

GeneID

23530.

KEGG

hsa:23530.

UCSC

uc003joe.3. human.

Organism-specific databases

CTD

23530.

GeneCards

GC05P043638.

H-InvDB

HIX0032203.

HGNC

HGNC:7863. NNT.

HPA

CAB004975.
HPA004829.

MIM

607878. gene.
614736. phenotype.

neXtProt

NX_Q13423.

Orphanet

361. Familial glucocorticoid deficiency.

PharmGKB

PA31667.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG1282.

HOGENOM

HOG000160623.

HOVERGEN

HBG006511.

InParanoid

Q13423.

KO

K00323.

OMA

KVRESYQ.

OrthoDB

EOG4X3H0K.

PhylomeDB

Q13423.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.

Gene expression databases

ArrayExpress

Q13423.

Bgee

Q13423.

CleanEx

HS_NNT.

Genevestigator

Q13423.

GermOnline

ENSG00000112992. Homo sapiens.

Family and domain databases

InterPro

IPR008142. 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]

Pfam

PF01262. AlaDh_PNT_C. 1 hit.
PF05222. AlaDh_PNT_N. 1 hit.
PF12769. DUF3814. 1 hit.
PF02233. PNTB. 1 hit.
[Graphical view]

SMART

SM01002. AlaDh_PNT_C. 1 hit.
SM01003. AlaDh_PNT_N. 1 hit.
[Graphical view]

TIGRFAMs

TIGR00561. pntA. 1 hit.

PROSITE

PS00836. ALADH_PNT_1. 1 hit.
PS00837. ALADH_PNT_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB00157. NADH.

EvolutionaryTrace

Q13423.

GenomeRNAi

23530.

NextBio

46004.

SOURCE

Search...

Entry information

Entry name

NNTM_HUMAN

Accession

Primary (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:	May 29, 2013
This is version 134 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.