O95989 (NUDT3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Diphosphoinositol polyphosphate phosphohydrolase 1
Short name=DIPP-1
EC=3.6.1.52

Alternative name(s):
Diadenosine 5',5'''-P1,P6-hexaphosphate hydrolase 1
EC=3.6.1.-
Nucleoside diphosphate-linked moiety X motif 3
Short name=Nudix motif 3

Gene names

Name:	NUDT3
Synonyms:	DIPP, DIPP1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	172 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Cleaves a beta-phosphate from the diphosphate groups in PP-InsP5 (diphosphoinositol pentakisphosphate) and [PP]2-InsP4 (bisdiphosphoinositol tetrakisphosphate), suggesting that it may play a role in signal transduction. InsP6 (inositol hexakisphophate) is not a substrate. Acts as a negative regulator of the ERK1/2 pathway. Also able to catalyze the hydrolysis of dinucleoside oligophosphates, with Ap6A and Ap5A being the preferred substrates. The major reaction products are ADP and p4a from Ap6A and ADP and ATP from Ap5A. Also able to hydrolyze 5-phosphoribose 1-diphosphate. Ref.1
Catalytic activity	Diphospho-myo-inositol polyphosphate + H2O = myo-inositol polyphosphate + phosphate. Ref.1 Ref.7 Ref.9
Cofactor	Binds 3 magnesium ions per subunit. Ref.11
Enzyme regulation	Inhibited by fluoride and InsP6. Ref.11
Subunit structure	Monomer By similarity.
Subcellular location	Cytoplasm Probable.
Tissue specificity	Widely expressed. Expressed at higher level in brain, heart, pancreas and liver. Also expressed in placenta, lung and kidney. Ref.1
Sequence similarities	Belongs to the Nudix hydrolase family. DIPP subfamily. Contains 1 nudix hydrolase domain.
Biophysicochemical properties	Kinetic parameters: KM=5.9 µM for Ap6A Ref.1 Ref.7 Ref.9 KM=7.7 µM for Ap5A KM=38 mM for 5-phosphoribose 1-diphosphate KM=4.2 nM for PP-InsP5 pH dependence: Optimum pH is 7-7.5.

Ontologies

Keywords
Cellular component	Cytoplasm
Ligand	Magnesium Metal-binding
Molecular function	Hydrolase
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	cell-cell signaling Traceable author statement. Source: ProtInc diadenosine polyphosphate catabolic process Traceable author statement. Source: ProtInc diphosphoinositol polyphosphate catabolic process Inferred from direct assay Ref.8. Source: UniProtKB
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	diphosphoinositol-polyphosphate diphosphatase activity Inferred from direct assay Ref.8. Source: UniProtKB magnesium ion binding Inferred from direct assay Ref.11. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 172

172

Diphosphoinositol polyphosphate phosphohydrolase 1

PRO_0000057055

Regions

Domain

17 – 142

126

Nudix hydrolase

Region

18 – 20

3

Substrate binding

Region

89 – 91

3

Substrate binding

Motif

51 – 72

22

Nudix box

Sites

Active site

69

1

Proton acceptor Probable

Metal binding

50

1

Magnesium 1; via carbonyl oxygen

Metal binding

66

1

Magnesium 2

Metal binding

66

1

Magnesium 3

Metal binding

70

1

Magnesium 1

Binding site

10

1

Substrate

Binding site

41

1

Substrate

Experimental info

Mutagenesis

50

1

G → A or V: Loss of function. Ref.8

Mutagenesis

51

1

G → A: Loss of function. Ref.8

Mutagenesis

52

1

G → A or V: Loss of function. Ref.8

Mutagenesis

66

1

E → Q: Loss of function. Ref.8

Mutagenesis

70

1

E → Q: Loss of function. Ref.1

Mutagenesis

72

1

G → A: Loss of function. Ref.8

Mutagenesis

75

1

G → A: Loss of function. Ref.8

Mutagenesis

78

1

G → A: No effect. Ref.8

Mutagenesis

78

1

G → V: Loss of function. Ref.8

Mutagenesis

82

1

G → A: Loss of function. Ref.8

Mutagenesis

84

1

F → Y: Induces a strong decrease in Ap6A and [PP]-InsP4 hydrolysis, while it only weakly affects PP-InsP5 hydrolysis. Ref.8

Mutagenesis

91

1

H → L: Induces a strong decrease in Ap6A and [PP]-InsP4 hydrolysis, while it only weakly affects PP-InsP5 hydrolysis. Ref.8

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

172

Helix Strand Turn

Details...

Beta strand

18 – 28

11

Beta strand

33 – 38

6

Beta strand

45 – 47

3

Beta strand

50 – 52

3

Helix

59 – 71

13

Beta strand

73 – 86

14

Turn

87 – 90

4

Beta strand

91 – 103

13

Helix

108 – 113

6

Beta strand

117 – 121

5

Helix

122 – 129

8

Turn

130 – 132

3

Helix

134 – 138

5

Sequences

	Sequence		Length	Mass (Da)
	O95989 [UniParc]. Last modified May 1, 1999. Version 1. Checksum: DE823FECF5C6438A	FASTA	172	19,471
	10 20 30 40 50 60 MMKLKSNQTR TYDGDGYKKR AACLCFRSES EEEVLLVSSS RHPDRWIVPG GGMEPEEEPS 70 80 90 100 110 120 VAAVREVCEE AGVKGTLGRL VGIFENQERK HRTYVYVLIV TEVLEDWEDS VNIGRKREWF 130 140 150 160 170 KIEDAIKVLQ YHKPVQASYF ETLRQGYSAN NGTPVVATTY SVSAQSSMSG IR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A novel context for the 'MutT' module, a guardian of cell integrity, in a diphosphoinositol polyphosphate phosphohydrolase." Safrany S.T., Caffrey J.J., Yang X., Bembenek M.E., Moyer M.B., Burkhart W.A., Shears S.B. EMBO J. 17:6599-6607(1998) [PubMed: 9822604] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, ENZYME ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, TISSUE SPECIFICITY, MUTAGENESIS OF GLU-70. Tissue: Uterus.
[2]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Amygdala.
[4]	"The DNA sequence and analysis of human chromosome 6." Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S. Nature 425:805-811(2003) [PubMed: 14574404] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Uterus.
[7]	"The diadenosine hexaphosphate hydrolases from Schizosaccharomyces pombe and Saccharomyces cerevisiae are homologues of the human diphosphoinositol polyphosphate phosphohydrolase. Overlapping substrate specificities in a MutT-type protein." Safrany S.T., Ingram S.W., Cartwright J.L., Falck J.R., McLennan A.G., Barnes L.D., Shears S.B. J. Biol. Chem. 274:21735-21740(1999) [PubMed: 10419486] [Abstract] Cited for: ENZYME ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES.
[8]	"Site-directed mutagenesis of diphosphoinositol polyphosphate phosphohydrolase, a dual specificity NUDT enzyme that attacks diadenosine polyphosphates and diphosphoinositol polyphosphates." Yang X., Safrany S.T., Shears S.B. J. Biol. Chem. 274:35434-35440(1999) [PubMed: 10585413] [Abstract] Cited for: MUTAGENESIS OF GLY-50; GLY-51; GLY-52; GLU-66; GLY-72; GLY-75; GLY-78; GLY-82; PHE-84 AND HIS-91.
[9]	"Nudix hydrolases that degrade dinucleoside and diphosphoinositol polyphosphates also have 5-phosphoribosyl 1-pyrophosphate (PRPP) pyrophosphatase activity that generates the glycolytic activator ribose 1,5-bisphosphate." Fisher D.I., Safrany S.T., Strike P., McLennan A.G., Cartwright J.L. J. Biol. Chem. 277:47313-47317(2002) [PubMed: 12370170] [Abstract] Cited for: ENZYME ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES.
[10]	"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: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[11]	"Crystal structure of human diphosphoinositol phosphatase 1." Thorsell A.G., Persson C., Graslund S., Hammarstrom M., Busam R.D., Hallberg B.M. Proteins 77:242-246(2009) [PubMed: 19585659] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.25 ANGSTROMS) IN COMPLEX WITH MAGNESIUM IONS; FLUORIDE AND INOSITOL HEXAKISPHOSPHATE, COFACTOR, ENZYME REGULATION.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF062529 mRNA. Translation: AAC83224.1.
AF062530 mRNA. Translation: AAC83225.1.
BT019984 mRNA. Translation: AAV38787.1.
BT019985 mRNA. Translation: AAV38788.1.
AK313440 mRNA. Translation: BAG36231.1.
Z98036, AL355855 Genomic DNA. Translation: CAI19715.1.
AL355855, Z98036 Genomic DNA. Translation: CAH72222.1.
CH471081 Genomic DNA. Translation: EAX03781.1.
BC007727 mRNA. Translation: AAH07727.1.

IPI

IPI00009148.

RefSeq

NP_006694.1. NM_006703.3.

UniGene

Hs.188882.
Hs.728786.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2FVV	X-ray	1.25	A	1-172	[»]
2Q9P	X-ray	1.65	A	1-172	[»]

ProteinModelPortal

O95989.

SMR

O95989. Positions 8-142.

ModBase

Search...

Protein-protein interaction databases

IntAct

O95989. 7 interactions.

MINT

MINT-1412881.

STRING

O95989.

PTM databases

PhosphoSite

O95989.

Proteomic databases

PeptideAtlas

O95989.

PRIDE

O95989.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000358797; ENSP00000351650; ENSG00000112664.

GeneID

11165.

KEGG

hsa:11165.

UCSC

uc003ojl.1. human.

Organism-specific databases

CTD

11165.

GeneCards

GC06M034302.

H-InvDB

HIX0200875.

HGNC

HGNC:8050. NUDT3.

MIM

609228. gene.

neXtProt

NX_O95989.

PharmGKB

PA31834.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG09180.

GeneTree

ENSGT00390000012928.

HOGENOM

HBG713158.

HOVERGEN

HBG053341.

InParanoid

O95989.

OMA

GCLANNG.

OrthoDB

EOG479F89.

PhylomeDB

O95989.

Enzyme and pathway databases

BioCyc

MetaCyc:ENSG00000112664-MONOMER.

Gene expression databases

ArrayExpress

O95989.

Bgee

O95989.

CleanEx

HS_NUDT3.

Genevestigator

O95989.

GermOnline

ENSG00000112664. Homo sapiens.

Family and domain databases

InterPro

IPR020084. NUDIX_hydrolase_CS.
IPR000086. NUDIX_hydrolase_dom.
IPR015797. NUDIX_hydrolase_dom-like.
[Graphical view]

Gene3D

G3DSA:3.90.79.10. NUDIX_hydrolase. 1 hit.

KO

K07766.

Pfam

PF00293. NUDIX. 1 hit.
[Graphical view]

SUPFAM

SSF55811. NUDIX_hydrolase. 1 hit.

PROSITE

PS51462. NUDIX. 1 hit.
PS00893. NUDIX_BOX. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

42479.

SOURCE

Search...

Entry information

Entry name

NUDT3_HUMAN

Accession

Primary (citable) accession number: O95989
Secondary accession number(s): B2R8N4

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 5, 2005
Last sequence update:	May 1, 1999
Last modified:	January 25, 2012
This is version 107 of the entry and version 1 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.