Reviewed, UniProtKB/Swiss-Prot P09467 (F16P1_HUMAN)

Names and origin

Protein names

Recommended name:
    Fructose-1,6-bisphosphatase 1
      Short name=FBPase 1
    EC=3.1.3.11
Alternative name(s):
    D-fructose-1,6-bisphosphate 1-phosphohydrolase 1

Gene names

Name:	FBP1
Synonyms:	FBP

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	338 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)

Catalytic activity	D-fructose 1,6-bisphosphate + H2O = D-fructose 6-phosphate + phosphate.
Cofactor	Binds 3 magnesium ions per subunit By similarity.
Enzyme regulation	Subject to complex allosteric regulation. The enzyme can assume an active R-state, or an inactive T-state. Intermediate conformations may exist. AMP acts as allosteric inhibitor. AMP binding affects the turnover of bound substrate and not the affinity for substrate. Fructose-2,6-biphosphate acts as competitive inhibitor. Fructose-2,6-biphosphate and AMP have synergistic effects. Ref.12 Ref.13 Ref.14 Ref.15
Pathway	Carbohydrate biosynthesis; gluconeogenesis.
Subunit structure	Homotetramer. Ref.12 Ref.13 Ref.14 Ref.15
Involvement in disease	Defects in FBP1 are the cause of fructose-1,6-bisphosphatase deficiency (FBPD) [MIM:229700]. FBPD is inherited as an autosomal recessive disorder mainly in the liver and causes life-threatening episodes of hypoglycemia and metabolic acidosis (lactacidemia) in newborn infants or young children. Ref.16 Ref.17
Sequence similarities	Belongs to the FBPase class 1 family.
Sequence caution	The sequence AAC50207.1 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
Biological process	Carbohydrate metabolism Gluconeogenesis
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Ligand	Magnesium Metal-binding
Molecular function	Hydrolase
Technical term	3D-structure Allosteric enzyme Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	fructose metabolic process Ref.4 Traceable author statement. Source: ProtInc gluconeogenesis Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytosol Ref.16 Inferred from Experiment. Source: Reactome mitochondrion Inferred from direct assay. Source: HPA
Molecular function	fructose 1,6-bisphosphate 1-phosphatase activity Ref.16 Inferred from Experiment. Source: Reactome fructose-2,6-bisphosphate 2-phosphatase activity Ref.2 Traceable author statement. Source: ProtInc identical protein binding Inferred from physical interaction. Source: IntAct magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		2	EBI-712740,EBI-712740
BIN1	O00499	3	EBI-712740,EBI-719094

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.2

Chain

2 – 338

337

Fructose-1,6-bisphosphatase 1

PRO_0000200498

Regions

Nucleotide binding

18 – 22

5

AMP

Nucleotide binding

28 – 32

5

AMP

Nucleotide binding

113 – 114

2

AMP

Region

122 – 125

4

Substrate binding

Region

213 – 216

4

Substrate binding

Region

244 – 249

6

Substrate binding

Region

275 – 277

3

Substrate binding

Sites

Metal binding

69

1

Magnesium 1 By similarity

Metal binding

98

1

Magnesium 1 By similarity

Metal binding

98

1

Magnesium 2

Metal binding

119

1

Magnesium 2

Metal binding

119

1

Magnesium 3

Metal binding

121

1

Magnesium 2; via carbonyl oxygen

Metal binding

122

1

Magnesium 3

Metal binding

281

1

Magnesium 3

Binding site

141

1

AMP

Binding site

265

1

Substrate

Natural variations

Natural variant

164

1

G → S in FBPD. Ref.16

VAR_002380

Natural variant

177

1

A → D in FBPD. Ref.16

VAR_002381

Natural variant

194

1

F → S in FBPD. Ref.17

VAR_038812

Natural variant

218

1

K → R: dbSNP rs1769259. Ref.7 Ref.8 Ref.9

VAR_022212

Natural variant

233

1

F → I: dbSNP rs2297085. Ref.7

VAR_022213

Natural variant

255

1

R → L: dbSNP rs28369761. Ref.7

VAR_022214

Natural variant

284

1

P → R in FBPD. Ref.17

VAR_038813

Natural variant

325

1

V → A Ref.16

VAR_002382

Experimental info

Mutagenesis

119

1

D → A: Reduced activity.

Mutagenesis

122

1

D → A: Reduced activity.

Sequence conflict

215

1

G → A Ref.2

Sequence conflict

215

1

G → A Ref.5

Sequence conflict

337

1

A → G in AAC25774. Ref.5

Secondary structure

1

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338

Helix Strand Turn

Details...

Helix

14 – 25

12

Helix

30 – 49

20

Turn

50 – 53

4

Helix

54 – 57

4

Turn

58 – 61

4

Helix

74 – 87

14

Turn

88 – 90

3

Beta strand

92 – 97

6

Helix

108 – 110

3

Beta strand

113 – 122

10

Helix

124 – 129

6

Beta strand

133 – 141

9

Helix

150 – 152

3

Helix

157 – 159

3

Beta strand

161 – 178

18

Beta strand

181 – 187

7

Turn

189 – 191

3

Beta strand

194 – 200

7

Beta strand

208 – 211

4

Helix

214 – 219

6

Helix

222 – 232

11

Helix

249 – 259

11

Beta strand

262 – 265

4

Beta strand

275 – 277

3

Turn

278 – 281

4

Helix

282 – 291

10

Beta strand

295 – 297

3

Beta strand

299 – 302

4

Helix

303 – 305

3

Beta strand

317 – 320

4

Helix

322 – 333

12

Sequences

	Sequence		Length	Mass (Da)
	P09467-1 [UniParc]. Last modified January 23, 2007. Version 4. Checksum: BDE269BCBB359271	FASTA	338	36,814
	10 20 30 40 50 60 MADQAPFDTD VNTLTRFVME EGRKARGTGE LTQLLNSLCT AVKAISSAVR KAGIAHLYGI 70 80 90 100 110 120 AGSTNVTGDQ VKKLDVLSND LVMNMLKSSF ATCVLVSEED KHAIIVEPEK RGKYVVCFDP 130 140 150 160 170 180 LDGSSNIDCL VSVGTIFGIY RKKSTDEPSE KDALQPGRNL VAAGYALYGS ATMLVLAMDC 190 200 210 220 230 240 GVNCFMLDPA IGEFILVDKD VKIKKKGKIY SLNEGYAKDF DPAVTEYIQR KKFPPDNSAP 250 260 270 280 290 300 YGARYVGSMV ADVHRTLVYG GIFLYPANKK SPNGKLRLLY ECNPMAYVME KAGGMATTGK 310 320 330 EAVLDVIPTD IHQRAPVILG SPDDVLEFLK VYEKHSAQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Activation of the fructose 1,6-bisphosphatase gene by 1,25-dihydroxyvitamin D3 during monocytic differentiation." Solomon D.H., Raynal M.-C., Tejwani G.A., Cayre Y.E. Proc. Natl. Acad. Sci. U.S.A. 85:6904-6908(1988) [PubMed: 2842796] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Isolation of a human liver fructose-1,6-bisphosphatase cDNA and expression of the protein in Escherichia coli. Role of Asp-118 and Asp-121 in catalysis." El-Maghrabi M.R., Gidh-Jain M., Austin L.R., Pilkis S.J. J. Biol. Chem. 268:9466-9472(1993) [PubMed: 8387495] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 2-11. Tissue: Liver.
[3]	"cDNA sequences encoding human fructose 1,6-bisphosphatase from monocytes, liver and kidney: application of monocytes to molecular analysis of human fructose 1,6-bisphosphatase deficiency." Kikawa Y., Inuzuka M., Takano T., Shigematsu Y., Nakai A., Yamamoto Y., Jin B.Y., Koga J., Taketo A., Sudo M. Biochem. Biophys. Res. Commun. 199:687-693(1994) [PubMed: 8135811] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Kidney, Liver and Monocyte.
[4]	"Human fructose-1,6-bisphosphatase gene (FBP1): exon-intron organization, localization to chromosome bands 9q22.2-q22.3, and mutation screening in subjects with fructose-1,6-bisphosphatase deficiency." El-Maghrabi M.R., Lang A.J., Jiang W., Yamagata K., Stoffel M., Takeda J., Fernald A.A., le Beau M.M., Bell G.I., Baker L., Pilkis S.J. Genomics 27:520-525(1995) [PubMed: 7558035] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Liver.
[5]	"cDNA sequence and kinetic properties of human lung fructose(1, 6)bisphosphatase." Skalecki K., Rakus D., Wisniewski J.R., Kolodziej J., Dzugaj A. Arch. Biochem. Biophys. 365:1-9(1999) [PubMed: 10222032] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION. Tissue: Lung.
[6]	Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Thymus.
[7]	NIEHS SNPs program Submitted (DEC-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ARG-218; ILE-233 AND LEU-255.
[8]	"DNA sequence and analysis of human chromosome 9." Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., Bagguley C.L. , Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., Dunham I. Nature 429:369-374(2004) [PubMed: 15164053] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT ARG-218.
[9]	"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], VARIANT ARG-218. Tissue: Urinary bladder.
[10]	"Liver fructose-1,6-bisphosphatase cDNA: trans-complementation of fission yeast and characterization of two human transcripts." Bertolotti R., Armbruster-Hilbert L., Okayama H. Differentiation 59:51-60(1995) [PubMed: 7589895] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 320-338. Tissue: Liver.
[11]	"Crystallographic studies of the catalytic mechanism of the neutral form of fructose-1,6-bisphosphatase." Zhang Y., Liang J.-Y., Huang S., Ke H., Lipscomb W.N. Biochemistry 32:1844-1857(1993) [PubMed: 8382525] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) IN COMPLEXES WITH MAGNESIUM IONS AND SUBSTRATE ANALOGS, COFACTOR.
[12]	"Crystal structure of fructose-1,6-bisphosphatase complexed with fructose 2,6-bisphosphate, AMP, and Zn2+ at 2.0-A resolution: aspects of synergism between inhibitors." Xue Y., Huang S., Liang J.-Y., Zhang Y., Lipscomb W.N. Proc. Natl. Acad. Sci. U.S.A. 91:12482-12486(1994) [PubMed: 7809062] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) IN COMPLEX WITH FRUCTOSE-2,6-BISPHOSPHATE; AMP AND ZINC, SUBUNIT, COFACTOR, ENZYME REGULATION.
[13]	"Benzoxazole benzenesulfonamides as allosteric inhibitors of fructose-1,6-bisphosphatase." Lai C., Gum R.J., Daly M., Fry E.H., Hutchins C., Abad-Zapatero C., von Geldern T.W. Bioorg. Med. Chem. Lett. 16:1807-1810(2006) [PubMed: 16446092] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.81 ANGSTROMS) IN COMPLEX WITH BENZOXAZOLE BENZENESULFONAMIDES, SUBUNIT, ENZYME REGULATION.
[14]	"Benzoxazole benzenesulfonamides are novel allosteric inhibitors of fructose-1,6-bisphosphatase with a distinct binding mode." von Geldern T.W., Lai C., Gum R.J., Daly M., Sun C., Fry E.H., Abad-Zapatero C. Bioorg. Med. Chem. Lett. 16:1811-1815(2006) [PubMed: 16442285] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.95 ANGSTROMS) IN COMPLEX WITH BENZOXAZOLE BENZENESULFONAMIDES, SUBUNIT, ENZYME REGULATION.
[15]	"Allosteric FBPase inhibitors gain 10(5) times in potency when simultaneously binding two neighboring AMP sites." Hebeisen P., Kuhn B., Kohler P., Gubler M., Huber W., Kitas E., Schott B., Benz J., Joseph C., Ruf A. Bioorg. Med. Chem. Lett. 18:4708-4712(2008) [PubMed: 18650089] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) IN COMPLEX WITH AROMATIC SULFONYLUREA AMP ANALOGS, SUBUNIT, ENZYME REGULATION.
[16]	"Identification of genetic mutations in Japanese patients with fructose-1,6-bisphosphatase deficiency." Kikawa Y., Inuzuka M., Jin B.Y., Kaji S., Koga J., Yamamoto Y., Fujisawa K., Hata I., Nakai A., Shigematsu Y., Mizunuma H., Taketo A., Mayumi M., Sudo M. Am. J. Hum. Genet. 61:852-861(1997) [PubMed: 9382095] [Abstract] Cited for: VARIANTS FBPD SER-164 AND ASP-177, VARIANT ALA-325.
[17]	"Two newly identified genomic mutations in a Japanese female patient with fructose-1,6-bisphosphatase (FBPase) deficiency." Matsuura T., Chinen Y., Arashiro R., Katsuren K., Tamura T., Hyakuna N., Ohta T. Mol. Genet. Metab. 76:207-210(2002) [PubMed: 12126934] [Abstract] Cited for: VARIANTS FBPD SER-194 AND ARG-284.
+	Additional computationally mapped references.

Web resources

GeneReviews

NIEHS-SNPs

Wikipedia

Fructose bisphosphatase entry

Cross-references

Sequence databases

EMBLGenBankDDBJ

L10320 mRNA. Translation: AAA35817.1.
M19922 mRNA. Translation: AAA35517.1.
D26054 mRNA. Translation: BAA05051.1.
D26055 mRNA. Translation: BAA05052.1.
D26056 mRNA. Translation: BAA05053.1.
U21931 , U21925, U21926, U21927, U21929, U21930 Genomic DNA. Translation: AAC50207.1. Sequence problems.
AF073475 mRNA. Translation: AAC25774.1.
AK223395 mRNA. Translation: BAD97115.1.
AY866483 Genomic DNA. Translation: AAW34363.1.
AL161728 Genomic DNA. Translation: CAH72692.1.
BC012927 mRNA. Translation: AAH12927.1.
U47919 mRNA. Translation: AAA89098.1.
U47918 mRNA. Translation: AAA89097.1.

IPI

IPI00073772.

PIR

A46666.

RefSeq

NP_000498.2.

UniGene

Hs.494496

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1FTA	X-ray	2.30	A/B/C/D	2-337	[»]
2FHY	X-ray	2.95	A/D/H/L	1-338	[»]
2FIE	X-ray	2.81	A/D/H/L	1-338	[»]
2FIX	X-ray	3.50	A/D/H/L	1-338	[»]
2JJK	X-ray	2.00	A/B/C/D	1-338	[»]
2VT5	X-ray	2.20	A/B/C/D/E/F/G/H	1-338	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

P09467. 9 interactions.

PTM databases

PhosphoSite

P09467.

Proteomic databases

PRIDE

P09467.

Genome annotation databases

Ensembl

ENSG00000165140. Homo sapiens. [Contig view]

GeneID

2203.

KEGG

hsa:2203.

Organism-specific databases

GeneCards

GC09M096405.

H-InvDB

HIX0008191.

HGNC

HGNC:3606. FBP1.

HPA

HPA005857.
HPA012513.

MIM

229700. phenotype.
611570. gene.

Orphanet

348. Fructose-1,6-bisphosphatase deficiency.

PharmGKB

PA28018.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P09467.

HOVERGEN

P09467.

Enzyme and pathway databases

BRENDA

3.1.3.11. 247.

Reactome

REACT_474. Metabolism of carbohydrates.

Gene expression databases

ArrayExpress

P09467.

Bgee

P09467.

CleanEx

HS_FBP1.

GermOnline

ENSG00000165140. Homo sapiens.

Family and domain databases

InterPro

IPR000146. Fructose_bisphosphatase.
IPR017955. IMPase/FBPase.
[Graphical view]

PANTHER

PTHR11556. In_FB_phphtase. 1 hit.

Pfam

PF00316. FBPase. 1 hit.
[Graphical view]

PRINTS

PR00115. FBPHPHTASE.
PR00377. INFBPHPHTASE.

ProDom

PD001491. In_FB_phphtase. 1 hit.
[Graphical view] [Entries sharing at least one domain]

PROSITE

PS00124. FBPASE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00131. Adenosine monophosphate.

NextBio

8907.

SOURCE

Search...

Entry information

Entry name

F16P1_HUMAN

Accession

Primary (citable) accession number: P09467
Secondary accession number(s): O75571, Q53F94, Q96E46

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1989
Last sequence update:	January 23, 2007
Last modified:	July 7, 2009
This is version 110 of the entry and version 4 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)