Reviewed, UniProtKB/Swiss-Prot O95989 (NUDT3_HUMAN)

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) [Complete proteome]

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.
Sequence processing	The displayed sequence is not processed.
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 catalyzes 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.5 Ref.7
Cofactor	Magnesium By similarity.
Enzyme regulation	Inhibited by fluoride and InsP6 By similarity.
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.
Biophysicochemical properties	Kinetic parameters: KM=5.9 µM for Ap6A 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
Gene Ontology (GO)
Biological process	cell-cell signaling Ref.5 Traceable author statement. Source: ProtInc diadenosine polyphosphate catabolic process Ref.5 Traceable author statement. Source: ProtInc
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	diphosphoinositol-polyphosphate diphosphatase activity Ref.1 Traceable author statement. Source: ProtInc magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW
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

Motif

51 – 72

22

Nudix box

Sites

Metal binding

66

1

Magnesium Probable

Metal binding

70

1

Magnesium Probable

Site

84

1

Important for substrate recognition

Site

91

1

Important for substrate recognition

Experimental info

Mutagenesis

50

1

G → A or V: Loss of function. Ref.6

Mutagenesis

51

1

G → A: Loss of function. Ref.6

Mutagenesis

52

1

G → A or V: Loss of function. Ref.6

Mutagenesis

66

1

E → Q: Loss of function. Ref.6

Mutagenesis

70

1

E → Q: Loss of function. Ref.1

Mutagenesis

72

1

G → A: Loss of function. Ref.6

Mutagenesis

75

1

G → A: Loss of function. Ref.6

Mutagenesis

78

1

G → A: No effect. Ref.6

Mutagenesis

78

1

G → V: Loss of function. Ref.6

Mutagenesis

82

1

G → A: Loss of function. Ref.6

Mutagenesis

84

1

F → Y: Induces a strong decrease in Ap6A and [PP]-InsP4 hydrolysis, while it only weakly affects PP-InsP5 hydrolysis. Ref.6

Mutagenesis

91

1

H → L: Induces a strong decrease in Ap6A and [PP]-InsP4 hydrolysis, while it only weakly affects PP-InsP5 hydrolysis. Ref.6

Secondary structure

1

.

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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)
	O95989-1 [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]	"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].
[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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Uterus.
[5]	"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.
[6]	"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.
[7]	"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.
[8]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.

Cross-references

Sequence databases

EMBLGenBankDDBJ

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

IPI

IPI00009148.

RefSeq

NP_006694.1.

UniGene

Hs.188882

3D structure databases

PDBPDBe

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

ModBase

Search...

Protein-protein interaction databases

IntAct

O95989. 5 interactions.

PTM databases

PhosphoSite

O95989.

Proteomic databases

PeptideAtlas

O95989.

PRIDE

O95989.

Genome annotation databases

Ensembl

ENSG00000112664. Homo sapiens. [Contig view]

GeneID

11165.

KEGG

hsa:11165.

UCSC

uc003ojl.1. human.

Organism-specific databases

GeneCards

GC06M034363.

H-InvDB

HIX0005790.

HGNC

HGNC:8050. NUDT3.

MIM

609228. gene.

PharmGKB

PA31834.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

O95989.

HOVERGEN

O95989.

OMA

O95989. REVCEEX.

Enzyme and pathway databases

BRENDA

3.6.1.52. 247.

Gene expression databases

ArrayExpress

O95989.

Bgee

O95989.

CleanEx

HS_NUDT3.

GermOnline

ENSG00000112664. Homo sapiens.

Family and domain databases

InterPro

IPR000086. NUDIX_hydrolase_core.
[Graphical view]

Gene3D

G3DSA:3.90.79.10. NUDIX_hydrolase. 1 hit.

Pfam

PF00293. NUDIX. 1 hit.
[Graphical view]

PROSITE

PS00893. NUDIX. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

42479.

SOURCE

Search...

Entry information

Entry name

NUDT3_HUMAN

Accession

Primary (citable) accession number: O95989

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 5, 2005
Last sequence update:	May 1, 1999
Last modified:	July 7, 2009
This is version 81 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)