P31939 (PUR9_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Bifunctional purine biosynthesis protein PURH

Including the following 2 domains:

1. Phosphoribosylaminoimidazolecarboxamide formyltransferase
   EC=2.1.2.3
   Alternative name(s):
   5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase
   AICAR transformylase
2. IMP cyclohydrolase
   EC=3.5.4.10
   Alternative name(s):
   ATIC
   IMP synthase
   Inosinicase

Gene names

Name:	ATIC
Synonyms:	PURH
ORF Names:	OK/SW-cl.86

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	592 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Bifunctional enzyme that catalyzes 2 steps in purine biosynthesis. Ref.12
Catalytic activity	10-formyltetrahydrofolate + 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide = tetrahydrofolate + 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide. IMP + H2O = 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide.
Pathway	Purine metabolism; IMP biosynthesis via de novo pathway; 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide from 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide (10-formyl THF route): step 1/1. Purine metabolism; IMP biosynthesis via de novo pathway; IMP from 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide: step 1/1.
Subunit structure	Homodimer. Ref.11 Ref.12
Domain	The IMP cyclohydrolase activity resides in the N-terminal region.
Involvement in disease	AICAR transformylase/IMP cyclohydrolase deficiency (AICAR) [MIM:608688]: A neurologically devastating inborn error of purine biosynthesis. Patients excrete massive amounts of AICA-riboside in the urine and accumulate AICA-ribotide and its derivatives in erythrocytes and fibroblasts. AICAR causes profound mental retardation, epilepsy, dysmorphic features and congenital blindness. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.12 Ref.13
Sequence similarities	Belongs to the PurH family.

Ontologies

Keywords
Biological process	Purine biosynthesis
Coding sequence diversity	Polymorphism
Disease	Disease mutation Epilepsy
Molecular function	Hydrolase Transferase
PTM	Acetylation
Technical term	3D-structure Complete proteome Direct protein sequencing Multifunctional enzyme Reference proteome
Gene Ontology (GO)
Biological_process	'de novo' IMP biosynthetic process Inferred from electronic annotation. Source: UniProtKB-UniPathway brainstem development Inferred from electronic annotation. Source: Compara cerebellum development Inferred from electronic annotation. Source: Compara cerebral cortex development Inferred from electronic annotation. Source: Compara dihydrofolate metabolic process Inferred from electronic annotation. Source: Compara nucleoside metabolic process Inferred from electronic annotation. Source: Compara organ regeneration Inferred from electronic annotation. Source: Compara purine nucleobase metabolic process Traceable author statement. Source: Reactome purine ribonucleoside monophosphate biosynthetic process Traceable author statement. Source: Reactome response to inorganic substance Inferred from electronic annotation. Source: Compara tetrahydrofolate biosynthetic process Inferred from electronic annotation. Source: Compara
Cellular_component	cytosol Traceable author statement. Source: Reactome mitochondrion Inferred from electronic annotation. Source: Compara
Molecular_function	IMP cyclohydrolase activity Traceable author statement. Source: Reactome phosphoribosylaminoimidazolecarboxamide formyltransferase activity Traceable author statement. Source: Reactome
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 592

592

Bifunctional purine biosynthesis protein PURH

PRO_0000192156

Regions

Nucleotide binding

12 – 14

3

IMP

Nucleotide binding

34 – 37

4

IMP

Nucleotide binding

64 – 67

4

IMP

Nucleotide binding

101 – 104

4

IMP

Nucleotide binding

125 – 127

3

IMP

Region

207 – 208

2

AICAR binding

Sites

Active site

137

1

Proton acceptor Potential

Active site

267

1

Proton acceptor Probable

Binding site

316

1

AICAR; via carbonyl oxygen

Binding site

339

1

AICAR

Binding site

431

1

AICAR; shared with dimeric partner

Binding site

451

1

AICAR; shared with dimeric partner

Binding site

541

1

AICAR; via carbonyl oxygen; shared with dimeric partner

Binding site

588

1

AICAR; shared with dimeric partner

Site

266

1

Transition state stabilizer Potential

Amino acid modifications

Modified residue

199

1

N6-acetyllysine Ref.9

Natural variations

Natural variant

116

1

T → S.
Corresponds to variant rs2372536 [ dbSNP | Ensembl ].

VAR_019306

Natural variant

426

1

K → R in AICAR; loss of transformylase activity. Ref.13

VAR_019307

Experimental info

Sequence conflict

1 – 6

6

MAPGQL → MSSLS Ref.1

Sequence conflict

165

1

D → G in AAA97405. Ref.1

Secondary structure

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592

Helix Strand Turn

Details...

Beta strand

6 – 10

5

Helix

17 – 25

9

Turn

26 – 28

3

Beta strand

30 – 33

4

Helix

35 – 42

8

Turn

43 – 45

3

Helix

51 – 55

5

Turn

61 – 64

4

Beta strand

65 – 67

3

Helix

70 – 77

8

Helix

82 – 91

10

Beta strand

96 – 101

6

Helix

106 – 111

6

Helix

117 – 122

6

Helix

127 – 137

11

Turn

138 – 141

4

Beta strand

143 – 145

3

Helix

148 – 150

3

Helix

151 – 160

10

Beta strand

161 – 165

5

Helix

168 – 197

30

Turn

200 – 202

3

Beta strand

203 – 207

5

Beta strand

209 – 211

3

Beta strand

217 – 220

4

Beta strand

222 – 225

4

Beta strand

227 – 233

7

Helix

237 – 257

21

Beta strand

261 – 266

6

Beta strand

269 – 275

7

Helix

281 – 286

6

Helix

290 – 295

6

Helix

298 – 308

11

Turn

311 – 316

6

Beta strand

317 – 323

7

Helix

327 – 334

8

Beta strand

338 – 344

7

Helix

348 – 360

13

Beta strand

363 – 367

5

Beta strand

375 – 381

7

Beta strand

384 – 389

6

Helix

397 – 400

4

Helix

412 – 426

15

Beta strand

433 – 437

5

Beta strand

440 – 445

6

Helix

451 – 467

17

Helix

471 – 474

4

Helix

486 – 496

11

Helix

503 – 509

7

Beta strand

512 – 514

3

Helix

521 – 528

8

Beta strand

534 – 540

7

Beta strand

543 – 545

3

Helix

546 – 552

7

Turn

553 – 555

3

Beta strand

556 – 562

7

Helix

568 – 578

11

Beta strand

581 – 586

6

Sequences

	Sequence		Length	Mass (Da)
	P31939 [UniParc]. Last modified October 10, 2002. Version 3. Checksum: AD778892021F0888	FASTA	592	64,616
	10 20 30 40 50 60 MAPGQLALFS VSDKTGLVEF ARNLTALGLN LVASGGTAKA LRDAGLAVRD VSELTGFPEM 70 80 90 100 110 120 LGGRVKTLHP AVHAGILARN IPEDNADMAR LDFNLIRVVA CNLYPFVKTV ASPGVTVEEA 130 140 150 160 170 180 VEQIDIGGVT LLRAAAKNHA RVTVVCEPED YVVVSTEMQS SESKDTSLET RRQLALKAFT 190 200 210 220 230 240 HTAQYDEAIS DYFRKQYSKG VSQMPLRYGM NPHQTPAQLY TLQPKLPITV LNGAPGFINL 250 260 270 280 290 300 CDALNAWQLV KELKEALGIP AAASFKHVSP AGAAVGIPLS EDEAKVCMVY DLYKTLTPIS 310 320 330 340 350 360 AAYARARGAD RMSSFGDFVA LSDVCDVPTA KIISREVSDG IIAPGYEEEA LTILSKKKNG 370 380 390 400 410 420 NYCVLQMDQS YKPDENEVRT LFGLHLSQKR NNGVVDKSLF SNVVTKNKDL PESALRDLIV 430 440 450 460 470 480 ATIAVKYTQS NSVCYAKNGQ VIGIGAGQQS RIHCTRLAGD KANYWWLRHH PQVLSMKFKT 490 500 510 520 530 540 GVKRAEISNA IDQYVTGTIG EDEDLIKWKA LFEEVPELLT EAEKKEWVEK LTEVSISSDA 550 560 570 580 590 FFPFRDNVDR AKRSGVAYIA APSGSAADKV VIEACDELGI ILAHTNLRLF HH

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The human purH gene product, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase. Cloning, sequencing, expression, purification, kinetic analysis, and domain mapping." Rayl E.A., Moroson B.A., Beardsley G.P. J. Biol. Chem. 271:2225-2233(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Hepatoma.
[2]	"Isolation of human purH gene expressed in the rodent transformant cells by subtractive enrichment of 3'-untranslated region of human transcript." Yamauchi M., Seki N., Mita K., Saito T., Tsuji S., Hongo E., Morimyo M., Shiomi T., Koyama H. DNA Res. 2:269-275(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Testis.
[3]	"Characterization of molecularly cloned human 5-aminoimidazole-4-carboxamide ribonucleotide transformylase." Sugita T., Aya H., Ueno M., Ishizuka T., Kawashima K. J. Biochem. 122:309-313(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Placenta.
[4]	"Identification of immuno-peptidmics that are recognized by tumor-reactive CTL generated from TIL of colon cancer patients." Shichijo S., Itoh K. Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Colon adenocarcinoma.
[5]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract] 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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Pancreas.
[7]	Lubec G., Vishwanath V., Chen W.-Q., Sun Y. Submitted (DEC-2008) to UniProtKB Cited for: PROTEIN SEQUENCE OF 15-39; 91-97; 178-194; 208-225; 267-285 AND 417-426, MASS SPECTROMETRY. Tissue: Brain, Cajal-Retzius cell and Fetal brain cortex.
[8]	"Microsequences of 145 proteins recorded in the two-dimensional gel protein database of normal human epidermal keratinocytes." Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E., Vandekerckhove J. Electrophoresis 13:960-969(1992) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 178-189 AND 267-281. Tissue: Keratinocyte.
[9]	"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-199, MASS SPECTROMETRY.
[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] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[11]	"Structural insights into the human and avian IMP cyclohydrolase mechanism via crystal structures with the bound XMP inhibitor." Wolan D.W., Cheong C.-G., Greasley S.E., Wilson I.A. Biochemistry 43:1171-1183(2004) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) IN COMPLEX WITH XMP, SUBUNIT.
[12]	"Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase in complex with potent sulfonyl-containing antifolates." Cheong C.-G., Wolan D.W., Greasley S.E., Horton P.A., Beardsley G.P., Wilson I.A. J. Biol. Chem. 279:18034-18045(2004) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.55 ANGSTROMS) IN COMPLEX WITH AICAR; XMP AND THE INHIBITORS BW1540 AND BW2315, FUNCTION, SUBUNIT.
[13]	"AICA-ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC." Marie S., Heron B., Bitoun P., Timmerman T., Van Den Berghe G., Vincent M.-F. Am. J. Hum. Genet. 74:1276-1281(2004) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT AICAR ARG-426, CHARACTERIZATION OF VARIANT AICAR ARG-426.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U37436 mRNA. Translation: AAA97405.1.
D82348 mRNA. Translation: BAA11559.1.
D89976 mRNA. Translation: BAA21762.1.
AB062403 mRNA. Translation: BAB93490.1.
AC073284 Genomic DNA. Translation: AAY24062.1.
BC008879 mRNA. Translation: AAH08879.1.

IPI

IPI00289499.

PIR

JC4642.

RefSeq

NP_004035.2. NM_004044.6.

UniGene

Hs.90280.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1P4R	X-ray	2.55	A/B	1-592	[»]
1PKX	X-ray	1.90	A/B/C/D	1-592	[»]
1PL0	X-ray	2.60	A/B/C/D	1-592	[»]

ProteinModelPortal

P31939.

ModBase

Search...

Protein-protein interaction databases

IntAct

P31939. 4 interactions.

STRING

9606.ENSP00000236959.

PTM databases

PhosphoSite

P31939.

Polymorphism databases

DMDM

23831360.

2D gel databases

REPRODUCTION-2DPAGE

IPI00289499.

UCD-2DPAGE

P31939.

Proteomic databases

PaxDb

P31939.

PeptideAtlas

P31939.

PRIDE

P31939.

Protocols and materials databases

DNASU

471.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000236959; ENSP00000236959; ENSG00000138363.

GeneID

471.

KEGG

hsa:471.

UCSC

uc002vex.4. human.

Organism-specific databases

CTD

471.

GeneCards

GC02P216176.

HGNC

HGNC:794. ATIC.

HPA

CAB013462.
HPA021012.

MIM

601731. gene.
608688. phenotype.

neXtProt

NX_P31939.

Orphanet

250977. AICA-ribosiduria.

PharmGKB

PA25094.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0138.

HOGENOM

HOG000230372.

HOVERGEN

HBG006912.

InParanoid

P31939.

KO

K00602.

OMA

DLLFAWK.

OrthoDB

EOG43BMNG.

PhylomeDB

P31939.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.

SABIO-RK

P31939.

UniPathway

UPA00074; UER00133.
UPA00074; UER00135.

Gene expression databases

ArrayExpress

P31939.

Bgee

P31939.

CleanEx

HS_ATIC.

Genevestigator

P31939.

GermOnline

ENSG00000138363. Homo sapiens.

Family and domain databases

Gene3D

1.10.287.440. 1 hit.
3.40.140.20. 3 hits.
3.40.50.1380. 1 hit.

InterPro

IPR024051. AICAR_Tfase_dom.
IPR024050. AICAR_Tfase_insert_dom.
IPR002695. AICARFT_IMPCHas.
IPR016193. Cytidine_deaminase-like.
IPR011607. MGS-like_dom.
[Graphical view]

PANTHER

PTHR11692. PTHR11692. 1 hit.

Pfam

PF01808. AICARFT_IMPCHas. 1 hit.
PF02142. MGS. 1 hit.
[Graphical view]

PIRSF

PIRSF000414. AICARFT_IMPCHas. 1 hit.

SMART

SM00798. AICARFT_IMPCHas. 1 hit.
SM00851. MGS. 1 hit.
[Graphical view]

SUPFAM

SSF53927. Cytidine_deaminase-like. 1 hit.
SSF52335. MGS-like_dom. 1 hit.

TIGRFAMs

TIGR00355. purH. 1 hit.

ProtoNet

Search...

Other

BindingDB

P31939.

ChEMBL

CHEMBL2518.

ChiTaRS

ATIC. human.

DrugBank

DB00116. Tetrahydrofolic acid.

EvolutionaryTrace

P31939.

GenomeRNAi

471.

NextBio

1945.

SOURCE

Search...

Entry information

Entry name

PUR9_HUMAN

Accession

Primary (citable) accession number: P31939
Secondary accession number(s): Q13856, Q53S28

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1993
Last sequence update:	October 10, 2002
Last modified:	May 1, 2013
This is version 139 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.