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AKR1B1

Available structures

Ortholog search: PDBe RCSB

List of PDB id codes

2PDQ, 1IEI, 2ACQ, 2FZB, 2IKH, 2PDH, 3LD5, 2IQ0, 1T40, 2PDG, 2PDB, 3GHR, 2NVD, 2PD5, 2PDU, 3M4H, 4GCA, 2PDX, 2I17, 1US0, 1AZ1, 2R24, 3M64, 1MAR, 3ONC, 1Z3N, 3ONB, 2ACR, 2DUZ, 2DUX, 2HVO, 2FZ8, 4PUW, 4XZH, 4QBX, 4JIR, 2PD9, 3LQL, 1ABN, 2PDW, 4PR4, 2PDI, 3LEP, 2PDJ, 4PUU, 2DV0, 3LEN, 3G5E, 1EF3, 4LB3, 2PDC, 3LBO, 2PDP, 2FZD, 4NKC, 2PZN, 2ISF, 3RX4, 2PDL, 3Q65, 4PRT, 4Q7B, 4QX4, 2FZ9, 2IKJ, 2J8T, 4IGS, 2IS7, 3V35, 1Z8A, 1XGD, 3T42, 2QXW, 4QR6, 1X96, 4RPQ, 2HV5, 2NVC, 2F2K, 3BCJ, 3LZ3, 3V36, 2PDK, 3GHU, 3GHS, 2ACU, 2PDM, 4LAZ, 1T41, 2IKG, 3MB9, 2PDF, 4PRR, 2PDN, 3LQG, 4XZI, 3LZ5, 2AGT, 3S3G, 1PWL, 3M0I, 2PF8, 3RX2, 2IPW, 3MC5, 3DN5, 4QXI, 2HVN, 2INZ, 1X97, 2PDY, 3RX3, 1PWM, 4LBR, 3Q67, 4LAU, 1Z89, 2IKI, 3P2V, 1X98, 1AZ2, 2PFH, 3U2C, 2ACS, 3GHT, 4LB4, 2INE, 1EL3, 2I16, 2IQD, 2PEV, 4LBS, 1ADS, 4YU1, 4YS1

Identifiers

Aliases

AKR1B1, ADR, ALDR1, ALR2, AR, aldo-keto reductase family 1, member B1 (aldose reductase), aldo-keto reductase family 1 member B

External IDs

OMIM: 103880; MGI: 1353494; HomoloGene: 133743; GeneCards: AKR1B1; OMA:AKR1B1 - orthologs

Gene location (Human)

Chr.	Chromosome 7 (human)^[1]

Band	7q33	Start	134,442,356 bp^[1]
Band	7q33	End	134,459,284 bp^[1]

Gene location (Mouse)

Chr.	Chromosome 6 (mouse)^[2]

Band	6 14.87 cM\|6 B1	Start	34,279,369 bp^[2]
Band	6 14.87 cM\|6 B1	End	34,294,413 bp^[2]

RNA expression pattern

Bgee

Human

Mouse (ortholog)

Top expressed in

right adrenal cortex

left adrenal gland

left adrenal cortex

olfactory bulb

spinal ganglia

seminal vesicula

apex of heart

Skeletal muscle tissue of rectus abdominis

trigeminal ganglion

gastrocnemius muscle

Top expressed in

urinary bladder

primary oocyte

secondary oocyte

zygote

adrenal gland

quadriceps femoris muscle

spermatocyte

muscle tissue

skeletal muscle tissue

right kidney

More reference expression data

BioGPS


More reference expression data

Gene ontology
Molecular function	aldo-keto reductase (NADP) activity electron transfer activity oxidoreductase activity glyceraldehyde oxidoreductase activity alditol:NADP+ 1-oxidoreductase activity alcohol dehydrogenase (NADP+) activity retinal dehydrogenase activity allyl-alcohol dehydrogenase activity NADP-retinol dehydrogenase activity
Cellular component	mast cell granule Schwann cell microvillus Schmidt-Lanterman incisure nucleoplasm plasma membrane bounded cell projection cytoplasm perinuclear region of cytoplasm paranodal junction extracellular exosome extracellular space cytoplasm cytosol
Biological process	stress-activated protein kinase signaling cascade cellular response to peptide daunorubicin metabolic process doxorubicin metabolic process maternal process involved in female pregnancy monosaccharide metabolic process norepinephrine metabolic process fructose biosynthetic process response to thyroid hormone response to stress response to water deprivation cellular response to methylglyoxal response to organic substance C21-steroid hormone biosynthetic process tissue homeostasis inner medullary collecting duct development positive regulation of receptor signaling pathway via JAK-STAT positive regulation of smooth muscle cell proliferation cellular response to hydrogen peroxide sorbitol biosynthetic process renal water homeostasis regulation of urine volume negative regulation of apoptotic process renal system development carbohydrate metabolic process electron transport chain cellular hyperosmotic salinity response retinoid metabolic process metanephric collecting duct development retinol metabolic process
Sources:Amigo / QuickGO

Orthologs

Species

Human

Mouse

Entrez


231


11677

Ensembl


ENSG00000085662


ENSMUSG00000001642

UniProt


P15121


P45376

RefSeq (mRNA)


NM_001628 NM_001346142


NM_009658

RefSeq (protein)


NP_001333071 NP_001619


NP_033788

Location (UCSC)

Chr 7: 134.44 – 134.46 Mb

Chr 6: 34.28 – 34.29 Mb

PubMed search

^[3]

^[4]

Wikidata

View/Edit Human

View/Edit Mouse

Aldo-keto reductase family 1, member B1 (AKR1B1) is an gene in humans that encodes the enzyme aldose reductase.^[5]^[6] It is a reduced nicotinamide-adenine dinucleotide phosphate (NADPH)-dependent enzyme catalyzing the reduction of various aldehydes and ketones to the corresponding alcohol. The involvement of AKR1B1 in oxidative stress diseases, cell signal transduction, and cell proliferation process endows AKR1B1 with potential as a therapeutic target.

Structure

Gene

The AKR1B1 gene lies on the chromosome location of 7q33 and consists of 10 exons. There are a few putative pseudogenes for this gene, and one of them has been confirmed and mapped to chromosome 3.^[6]

Protein

AKR1B1 consists of 316 amino acid residues and weighs 35853Da. It does not possess the traditional dinucleotide binding fold. The way it binds NADPH differs from other nucleotide adenine dinucleotide-dependent enzymes. The active site pocket of human aldose reductase is relatively hydrophobic, lined by seven aromatic and four other non-polar residues.^[7]

Function

AR belongs to the aldehyde-keto reductase superfamily, with a widely expression in human organs including the kidney, lens, retina, nerve, heart, placenta, brain, skeletal muscle, testis, blood vessels, lung, and liver.^[8] It is a reduced nicotinamide-adenine dinucleotide phosphate (NADPH)-dependent enzyme catalyzing the reduction of various aldehydes and ketones to the corresponding alcohol. It also participates in glucose metabolism and osmoregulation and plays a protective role against toxic aldehydes derived from lipid peroxidation and steroidogenesis.^[9]

Clinical significance

Under diabetic conditions AR converts glucose into sorbitol, which is then converted to fructose. 20466987 It has been found to play an important role in many diabetes complications such as diabetes retinopathy and renopathy.^[10]^[11]^[12] It is also involved in many oxidative stress diseases, cell signal transduction, and cell proliferation process including cardiovascular disorders, sepsis, and cancer.^[13]

It has been reported that the action of AR contributes to the activation of retinal microglia, suggesting that inhibition of AR may be of a therapeutic importance to reduce inflammation associated with activation of RMG.^[14] Adapting AR inhibitors could as well prevent sepsis complications, prevent angiogenesis, ameliorate mild or asymptomatic diabetic cardiovascular autonomic neuropathy and may be a promising strategy for the treatment of endotoxemia and other ROS-induced inflammatory diseases.^[12]

Interactions

AKR1B1 has been found to interact with:

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000085662 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000001642 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Graham A, Heath P, Morten JE, Markham AF (March 1991). "The human aldose reductase gene maps to chromosome region 7q35". Human Genetics. 86 (5): 509–14. doi:10.1007/BF00194644. PMID 1901827. S2CID 34446965.
^ ^a ^b "Entrez Gene: AKR1B1 aldo-keto reductase family 1, member B1 (aldose reductase)".
^ Lee H (August 1998). "The structure and function of yeast xylose (aldose) reductases". Yeast. 14 (11): 977–84. doi:10.1002/(sici)1097-0061(199808)14:11<977::aid-yea302>3.0.co;2-j. PMID 9730277. S2CID 39792612.
^ O'connor T, Ireland LS, Harrison DJ, Hayes JD (October 1999). "Major differences exist in the function and tissue-specific expression of human aflatoxin B1 aldehyde reductase and the principal human aldo-keto reductase AKR1 family members". The Biochemical Journal. 343 Pt 2 (2): 487–504. doi:10.1042/bj3430487. PMC 1220579. PMID 10510318.
^ Lefrançois-Martinez AM, Bertherat J, Val P, Tournaire C, Gallo-Payet N, Hyndman D, Veyssière G, Bertagna X, Jean C, Martinez A (June 2004). "Decreased expression of cyclic adenosine monophosphate-regulated aldose reductase (AKR1B1) is associated with malignancy in human sporadic adrenocortical tumors". The Journal of Clinical Endocrinology and Metabolism. 89 (6): 3010–9. doi:10.1210/jc.2003-031830. PMID 15181092.
^ Park J, Kim H, Park SY, Lim SW, Kim YS, Lee DH, Roh GS, Kim HJ, Kang SS, Cho GJ, Jeong BY, Kwon HM, Choi WS (May 2014). "Tonicity-responsive enhancer binding protein regulates the expression of aldose reductase and protein kinase C δ in a mouse model of diabetic retinopathy". Experimental Eye Research. 122: 13–9. doi:10.1016/j.exer.2014.03.001. PMID 24631337.
^ Zhou M, Zhang P, Xu X, Sun X (April 2015). "The Relationship Between Aldose Reductase C106T Polymorphism and Diabetic Retinopathy: An Updated Meta-Analysis". Investigative Ophthalmology & Visual Science. 56 (4): 2279–89. doi:10.1167/iovs.14-16279. PMID 25722213.
^ ^a ^b ^c ^d ^e Grewal AS, Bhardwaj S, Pandita D, Lather V, Sekhon BS (2016-01-01). "Updates on Aldose Reductase Inhibitors for Management of Diabetic Complications and Non-diabetic Diseases". Mini Reviews in Medicinal Chemistry. 16 (2): 120–62. doi:10.2174/1389557515666150909143737. PMID 26349493.
^ Maccari R, Ottanà R (March 2015). "Targeting aldose reductase for the treatment of diabetes complications and inflammatory diseases: new insights and future directions". Journal of Medicinal Chemistry. 58 (5): 2047–67. doi:10.1021/jm500907a. PMID 25375908.
^ Chang KC, Ponder J, Labarbera DV, Petrash JM (May 2014). "Aldose reductase inhibition prevents endotoxin-induced inflammatory responses in retinal microglia". Investigative Ophthalmology & Visual Science. 55 (5): 2853–61. doi:10.1167/iovs.13-13487. PMC 4010364. PMID 24677107.
^ Fatmawati S, Ersam T, Yu H, Zhang C, Jin F, Shimizu K (September 2014). "20(S)-Ginsenoside Rh2 as aldose reductase inhibitor from Panax ginseng". Bioorganic & Medicinal Chemistry Letters. 24 (18): 4407–9. doi:10.1016/j.bmcl.2014.08.009. PMID 25152999.
^ Gupta S, Singh N, Jaggi AS (March 2014). "Alkaloids as aldose reductase inhibitors, with special reference to berberine". Journal of Alternative and Complementary Medicine. 20 (3): 195–205. doi:10.1089/acm.2013.0088. PMID 24236461.

External links

Human AKR1B1 genome location and AKR1B1 gene details page in the UCSC Genome Browser.
Human AR genome location and AR gene details page in the UCSC Genome Browser.

PDB gallery

1abn: THE CRYSTAL STRUCTURE OF THE ALDOSE REDUCTASE NADPH BINARY COMPLEX
1ads: AN UNLIKELY SUGAR SUBSTRATE SITE IN THE 1.65 ANGSTROMS STRUCTURE OF THE HUMAN ALDOSE REDUCTASE HOLOENZYME IMPLICATED IN DIABETIC COMPLICATIONS
1az1: ALRESTATIN BOUND TO C298A/W219Y MUTANT HUMAN ALDOSE REDUCTASE
1az2: CITRATE BOUND, C298A/W219Y MUTANT HUMAN ALDOSE REDUCTASE
1ef3: FIDARESTAT BOUND TO HUMAN ALDOSE REDUCTASE
1el3: HUMAN ALDOSE REDUCTASE COMPLEXED WITH IDD384 INHIBITOR
1iei: CRYSTAL STRUCTURE OF HUMAN ALDOSE REDUCTASE COMPLEXED WITH THE INHIBITOR ZENARESTAT.
1mar: REFINED 1.8 ANGSTROMS STRUCTURE OF HUMAN ALDOSE REDUCTASE COMPLEXED WITH THE POTENT INHIBITOR ZOPOLRESTAT
1pwl: Crystal structure of human Aldose Reductase complexed with NADP and Minalrestat
1pwm: Crystal structure of human Aldose Reductase complexed with NADP and Fidarestat
1t40: Crystal structure of human aldose reductase complexed with NADP and IDD552 at ph 5
1t41: Crystal structure of human aldose reductase complexed with NADP and IDD552
1us0: HUMAN ALDOSE REDUCTASE IN COMPLEX WITH NADP+ AND THE INHIBITOR IDD594 AT 0.66 ANGSTROM
1x96: Crystal structure of Aldose Reductase with citrates bound in the active site
1x97: Crystal structure of Aldose Reductase complexed with 2R4S (Stereoisomer of Fidarestat, 2S4S)
1x98: Crystal structure of Aldose Reductase complexed with 2S4R (Stereoisomer of Fidarestat, 2S4S)
1xgd: Apo R268A human aldose reductase
1z3n: Human aldose reductase in complex with NADP+ and the inhibitor lidorestat at 1.04 angstrom
1z89: Human Aldose Reductase complexed with novel Sulfonyl-pyridazinone Inhibitor
1z8a: Human Aldose Reductase complexed with novel Sulfonyl-pyridazinone Inhibitor
2acq: AN ANION BINDING SITE IN HUMAN ALDOSE REDUCTASE: MECHANISTIC IMPLICATIONS FOR THE BINDING OF CITRATE, CACODYLATE, AND GLUCOSE-6-PHOSPHATE
2acr: AN ANION BINDING SITE IN HUMAN ALDOSE REDUCTASE: MECHANISTIC IMPLICATIONS FOR THE BINDING OF CITRATE, CACODYLATE, AND GLUCOSE-6-PHOSPHATE
2acs: AN ANION BINDING SITE IN HUMAN ALDOSE REDUCTASE: MECHANISTIC IMPLICATIONS FOR THE BINDING OF CITRATE, CACODYLATE, AND GLUCOSE-6-PHOSPHATE
2acu: TYROSINE-48 IS THE PROTON DONOR AND HISTIDINE-110 DIRECTS SUBSTRATE STEREOCHEMICAL SELECTIVITY IN THE REDUCTION REACTION OF HUMAN ALDOSE REDUCTASE: ENZYME KINETICS AND THE CRYSTAL STRUCTURE OF THE Y48H MUTANT ENZYME
2agt: Aldose Reductase Mutant Leu 300 Pro complexed with Fidarestat
2dux: Crystal structure of human Aldose Reductase complexed with zopolrestat after 3 days soaking (3days_soaked_1)
2duz: Human Aldose Reductase complexed with inhibitor zopolrestat after 3 days soaking (3days_soaked_2)
2dv0: Human Aldose Reductase complexed with zopolrestat after 6 days soaking(6days_soaked_2)
2f2k: Aldose reductase tertiary complex with NADPH and DEG
2fz8: Human Aldose reductase complexed with inhibitor zopolrestat at 1.48 A(1 day soaking).
2fz9: Human Aldose Reductase complexed with inhibitor zopolrestat after six days soaking.
2fzb: Human Aldose Reductase complexed with four tolrestat molecules at 1.5 A resolution.
2fzd: Human aldose reductase complexed with tolrestat at 1.08 A resolution.
2hv5: Human Aldose Reductase complexed with inhibitor zopolrestat after three days soaking (3days_soaked_3)
2hvn: Human Aldose Reductase-zopolrestat complex obtained by cocrystallisation after one day (1day_cocryst)
2hvo: Human Aldose Reductase-zopolrestat complex obtained by cocrystallisation (10days_cocryst)
2i16: Human aldose reductase in complex with NADP+ and the inhibitor IDD594 at temperature of 15K
2i17: Human aldose reductase in complex with NADP+ and the inhibitor IDD594 at temperature of 60K
2ikg: Aldose reductase complexed with nitrophenyl-oxadiazol type inhibitor at 1.43 A
2ikh: Human aldose reductase complexed with nitrofuryl-oxadiazol inhibitor at 1.55 A
2iki: Human aldose reductase complexed with halogenated IDD-type inhibitor
2ikj: Human aldose reductase complexed with nitro-substituted IDD-type inhibitor
2ine: Crystal Structure of Aldose Reductase complexed with Phenylacetic Acid
2inz: Crystal Structure of Aldose Reductase complexed with 2-Hydroxyphenylacetic Acid
2ipw: Crystal Structure of C298A W219Y Aldose Reductase complexed with Dichlorophenylacetic acid
2iq0: Crystal Structure of Aldose Reductase complexed with Hexanoic Acid
2iqd: Crystal Structure of Aldose Reductase complexed with Lipoic Acid
2is7: Crystal Structure of Aldose Reductase complexed with Dichlorophenylacetic acid
2isf: Crystal Structure of C298A W219Y Aldose Reductase complexed with Phenylacetic Acid
2j8t: HUMAN ALDOSE REDUCTASE IN COMPLEX WITH NADP AND CITRATE AT 0.82 ANGSTROM
2nvc: Human Aldose Reductase complexed with novel naphtho[1,2-d]isothiazole acetic acid derivative (3)
2nvd: Human Aldose Reductase complexed with novel naphtho[1,2-d]isothiazole acetic acid derivative (2)
2pev: Complex of Aldose Reductase with NADP+ and simultaneously bound competitive inhibitors Fidarestat and IDD594. Concentration of Fidarestat in soaking solution exceeds concentration of IDD594.
2pf8: Complex of Aldose Reductase with NADP+ and simultaneously bound competitive inhibitors Fidarestat and IDD594. Concentration of Fidarestat in soaking solution is equal to concentration of IDD594.
2pfh: Complex of Aldose Reductase with NADP+ and simultaneously bound competitive inhibitors Fidarestat and IDD594. Concentration of Fidarestat in soaking solution is less than concentration of IDD594.

v t e Oxidoreductases: alcohol oxidoreductases (EC 1.1)
1.1.1: NAD/NADP acceptor	3-hydroxyacyl-CoA dehydrogenase 3-hydroxybutyryl-CoA dehydrogenase Alcohol dehydrogenase Aldo-keto reductase 1A1 1B1 1B10 1C1 1C3 1C4 7A2 Aldose reductase Beta-Ketoacyl ACP reductase Carbohydrate dehydrogenases Carnitine dehydrogenase D-malate dehydrogenase (decarboxylating) DXP reductoisomerase Glucose-6-phosphate dehydrogenase Glycerol-3-phosphate dehydrogenase HMG-CoA reductase IMP dehydrogenase Isocitrate dehydrogenase Lactate dehydrogenase L-threonine dehydrogenase L-xylulose reductase Malate dehydrogenase Malate dehydrogenase (decarboxylating) Malate dehydrogenase (NADP+) Malate dehydrogenase (oxaloacetate-decarboxylating) Malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+) Phosphogluconate dehydrogenase Sorbitol dehydrogenase Hydroxysteroid dehydrogenase: 3β 3β-HSD NSDHL 11β 11β-HSD1 11β-HSD2 17β
1.1.2: cytochrome acceptor	D-lactate dehydrogenase (cytochrome) D-lactate dehydrogenase (cytochrome c-553) Mannitol dehydrogenase (cytochrome)
1.1.3: oxygen acceptor	Glucose oxidase L-gulonolactone oxidase Xanthine oxidase Alcohol oxidase
1.1.4: disulfide as acceptor	Vitamin K epoxide reductase Vitamin-K-epoxide reductase (warfarin-insensitive)
1.1.5: quinone/similar acceptor	Malate dehydrogenase (quinone) Quinoprotein glucose dehydrogenase
1.1.99: other acceptors	Choline dehydrogenase L2HGDH

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

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