| Structural highlights
8k7k is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
AGAL_HUMAN Defects in GLA are the cause of Fabry disease (FD) [MIM:301500. FD is a rare X-linked sphingolipidosis disease where glycolipid accumulates in many tissues. The disease consists of an inborn error of glycosphingolipid catabolism. FD patients show systemic accumulation of globotriaoslyceramide (Gb3) and related glycosphingolipids in the plasma and cellular lysosomes throughout the body. Clinical recognition in males results from characteristic skin lesions (angiokeratomas) over the lower trunk. Patients may show ocular deposits, febrile episodes, and burning pain in the extremities. Death results from renal failure, cardiac or cerebral complications of hypertension or other vascular disease. Heterozygous females may exhibit the disorder in an attenuated form, they are more likely to show corneal opacities.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40]
Function
AGAL_HUMAN
Publication Abstract from PubMed
The use of pharmacological chaperones (PCs) to stabilize specific enzymes and impart a therapeutic benefit is an emerging strategy in drug discovery. However, designing molecules that can bind optimally to their targets at physiological pH remains a major challenge. Our previous study found that dibasic polyhydroxylated pyrrolidine 5 exhibited superior pH-selective inhibitory activity and chaperoning activity for human alpha-galactosidase A (alpha-Gal A) compared with its monobasic parent molecule, 4. To further investigate the role of different C-2 moieties on the pH-selectivity and protecting effects of these compounds, we designed and synthesized a library of monobasic and dibasic iminosugars, screened them for alpha-Gal A-stabilizing activity using thermal shift and heat-induced denaturation assays, and characterized the mechanistic basis for this stabilization using X-ray crystallography and binding assays. We noted that the dibasic iminosugars 5 and 20 protect alpha-Gal A from denaturation and inactivation at lower concentrations than monobasic or other N-substituted derivatives; a finding attributed to the nitrogen on the C-2 methylene of 5 and 20, which forms the bifurcated salt bridges (BSBs) with two carboxyl residues, E203 and D231. Additionally, the formation of BSBs at pH 7.0 and the electrostatic repulsion between the vicinal ammonium cations of dibasic iminosugars at pH 4.5 are responsible for their pH-selective binding to alpha-Gal A. Moreover, compounds 5 and 20 demonstrated promising results in improving enzyme replacement therapy and exhibited significant chaperoning effects in Fabry cells. These findings suggest amino-iminosugars 5 and 20 as useful models to demonstrate how an additional exocyclic amino group can improve their pH-selectivity and protecting effects, providing new insights for the design of pH-selective PCs.
Mechanistic Insights into Dibasic Iminosugars as pH-Selective Pharmacological Chaperones to Stabilize Human alpha-Galactosidase.,Li HY, Lin HY, Chang SK, Chiu YT, Hou CC, Ko TP, Huang KF, Niu DM, Cheng WC JACS Au. 2024 Feb 23;4(3):908-918. doi: 10.1021/jacsau.3c00684. eCollection 2024 , Mar 25. PMID:38559739[41]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ von Scheidt W, Eng CM, Fitzmaurice TF, Erdmann E, Hubner G, Olsen EG, Christomanou H, Kandolf R, Bishop DF, Desnick RJ. An atypical variant of Fabry's disease with manifestations confined to the myocardium. N Engl J Med. 1991 Feb 7;324(6):395-9. PMID:1846223 doi:http://dx.doi.org/10.1056/NEJM199102073240607
- ↑ Sakuraba H, Oshima A, Fukuhara Y, Shimmoto M, Nagao Y, Bishop DF, Desnick RJ, Suzuki Y. Identification of point mutations in the alpha-galactosidase A gene in classical and atypical hemizygotes with Fabry disease. Am J Hum Genet. 1990 Nov;47(5):784-9. PMID:2171331
- ↑ Bernstein HS, Bishop DF, Astrin KH, Kornreich R, Eng CM, Sakuraba H, Desnick RJ. Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene. J Clin Invest. 1989 Apr;83(4):1390-9. PMID:2539398 doi:http://dx.doi.org/10.1172/JCI114027
- ↑ Ishii S, Sakuraba H, Suzuki Y. Point mutations in the upstream region of the alpha-galactosidase A gene exon 6 in an atypical variant of Fabry disease. Hum Genet. 1992 Apr;89(1):29-32. PMID:1315715
- ↑ Eng CM, Resnick-Silverman LA, Niehaus DJ, Astrin KH, Desnick RJ. Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. Am J Hum Genet. 1993 Dec;53(6):1186-97. PMID:7504405
- ↑ Davies JP, Winchester BG, Malcolm S. Mutation analysis in patients with the typical form of Anderson-Fabry disease. Hum Mol Genet. 1993 Jul;2(7):1051-3. PMID:8395937
- ↑ Davies J, Christomanou H, Winchester B, Malcolm S. Detection of 8 new mutations in the alpha-galactosidase A gene in Fabry disease. Hum Mol Genet. 1994 Apr;3(4):667-9. PMID:8069316
- ↑ Eng CM, Niehaus DJ, Enriquez AL, Burgert TS, Ludman MD, Desnick RJ. Fabry disease: twenty-three mutations including sense and antisense CpG alterations and identification of a deletional hot-spot in the alpha-galactosidase A gene. Hum Mol Genet. 1994 Oct;3(10):1795-9. PMID:7531540
- ↑ Okumiya T, Ishii S, Takenaka T, Kase R, Kamei S, Sakuraba H, Suzuki Y. Galactose stabilizes various missense mutants of alpha-galactosidase in Fabry disease. Biochem Biophys Res Commun. 1995 Sep 25;214(3):1219-24. PMID:7575533 doi:http://dx.doi.org/10.1006/bbrc.1995.2416
- ↑ Okumiya T, Ishii S, Kase R, Kamei S, Sakuraba H, Suzuki Y. Alpha-galactosidase gene mutations in Fabry disease: heterogeneous expressions of mutant enzyme proteins. Hum Genet. 1995 May;95(5):557-61. PMID:7759078
- ↑ Madsen KM, Hasholt L, Sorensen SA, Fermer ML, Dahl N. Two novel mutations (L32P) and (G85N) among five different missense mutations in six Danish families with Fabry's disease. Hum Mutat. 1995;5(3):277-8. PMID:7599642 doi:http://dx.doi.org/10.1002/humu.1380050316
- ↑ Nakao S, Takenaka T, Maeda M, Kodama C, Tanaka A, Tahara M, Yoshida A, Kuriyama M, Hayashibe H, Sakuraba H, et al.. An atypical variant of Fabry's disease in men with left ventricular hypertrophy. N Engl J Med. 1995 Aug 3;333(5):288-93. PMID:7596372 doi:http://dx.doi.org/10.1056/NEJM199508033330504
- ↑ Sawada K, Mizoguchi K, Hishida A, Kaneko E, Koide Y, Nishimura K, Kimura M. Point mutation in the alpha-galactosidase A gene of atypical Fabry disease with only nephropathy. Clin Nephrol. 1996 May;45(5):289-94. PMID:8738659
- ↑ Davies JP, Eng CM, Hill JA, Malcolm S, MacDermot K, Winchester B, Desnick RJ. Fabry disease: fourteen alpha-galactosidase A mutations in unrelated families from the United Kingdom and other European countries. Eur J Hum Genet. 1996;4(4):219-24. PMID:8875188
- ↑ Cariolou MA, Christodoulides M, Manoli P, Kokkofitou A, Tsambaos D. Novel trinucleotide deletion in Fabry's disease. Hum Genet. 1996 Apr;97(4):468-70. PMID:8834244
- ↑ Germain D, Biasotto M, Tosi M, Meo T, Kahn A, Poenaru L. Fluorescence-assisted mismatch analysis (FAMA) for exhaustive screening of the alpha-galactosidase A gene and detection of carriers in Fabry disease. Hum Genet. 1996 Dec;98(6):719-26. PMID:8931708
- ↑ Blanch LC, Meaney C, Morris CP. A sensitive mutation screening strategy for Fabry disease: detection of nine mutations in the alpha-galactosidase A gene. Hum Mutat. 1996;8(1):38-43. PMID:8807334 doi:<38::AID-HUMU5>3.0.CO;2-L 10.1002/(SICI)1098-1004(1996)8:1<38::AID-HUMU5>3.0.CO;2-L
- ↑ Redonnet-Vernhet I, Ploos van Amstel JK, Jansen RP, Wevers RA, Salvayre R, Levade T. Uneven X inactivation in a female monozygotic twin pair with Fabry disease and discordant expression of a novel mutation in the alpha-galactosidase A gene. J Med Genet. 1996 Aug;33(8):682-8. PMID:8863162
- ↑ Takata T, Okumiya T, Hayashibe H, Shimmoto M, Kase R, Itoh K, Utsumi K, Kamei S, Sakuraba H. Screening and detection of gene mutations in Japanese patients with Fabry disease by non-radioactive single-stranded conformation polymorphism analysis. Brain Dev. 1997 Mar;19(2):111-6. PMID:9105656
- ↑ Eng CM, Ashley GA, Burgert TS, Enriquez AL, D'Souza M, Desnick RJ. Fabry disease: thirty-five mutations in the alpha-galactosidase A gene in patients with classic and variant phenotypes. Mol Med. 1997 Mar;3(3):174-82. PMID:9100224
- ↑ Chen CH, Shyu PW, Wu SJ, Sheu SS, Desnick RJ, Hsiao KJ. Identification of a novel point mutation (S65T) in alpha-galactosidase A gene in Chinese patients with Fabry disease. Mutations in brief no. 169. Online. Hum Mutat. 1998;11(4):328-30. PMID:9554750 doi:<328::AID-HUMU11>3.0.CO;2-N 10.1002/(SICI)1098-1004(1998)11:4<328::AID-HUMU11>3.0.CO;2-N
- ↑ Miyazaki T, Kajita M, Ohmori S, Mizutani N, Niwa T, Murata Y, Seo H. A novel mutation (E358K) in the alpha-galactosidase A gene detected in a Japanese family with Fabry disease. Hum Mutat. 1998;Suppl 1:S139-40. PMID:9452068
- ↑ Okumiya T, Kawamura O, Itoh K, Kase R, Ishii S, Kamei S, Sakuraba H. Novel missense mutation (M72V) of alpha-galactosidase gene and its expression product in an atypical Fabry hemizygote. Hum Mutat. 1998;Suppl 1:S213-6. PMID:9452090
- ↑ Guffon N, Froissart R, Chevalier-Porst F, Maire I. Mutation analysis in 11 French patients with Fabry disease. Hum Mutat. 1998;Suppl 1:S288-90. PMID:9452111
- ↑ Germain DP, Poenaru L. Fabry disease: identification of novel alpha-galactosidase A mutations and molecular carrier detection by use of fluorescent chemical cleavage of mismatches. Biochem Biophys Res Commun. 1999 Apr 21;257(3):708-13. PMID:10208848 doi:10.1006/bbrc.1999.0310
- ↑ Beyer EM, Karpova EA, Udalova OV, Ploos van Amstel JK, van Diggelen OP, Tsvetkova IV. The multiple cases of Fabry disease in a Russian family caused by an E341K amino acid substitution in the alpha-galactosidase A. Clin Chim Acta. 1999 Feb;280(1-2):81-9. PMID:10090526
- ↑ Kase R, Bierfreund U, Klein A, Kolter T, Utsumi K, Itoha K, Sandhoff K, Sakuraba H. Characterization of two alpha-galactosidase mutants (Q279E and R301Q) found in an atypical variant of Fabry disease. Biochim Biophys Acta. 2000 Jun 15;1501(2-3):227-35. PMID:10838196
- ↑ Topaloglu AK, Ashley GA, Tong B, Shabbeer J, Astrin KH, Eng CM, Desnick RJ. Twenty novel mutations in the alpha-galactosidase A gene causing Fabry disease. Mol Med. 1999 Dec;5(12):806-11. PMID:10666480
- ↑ Lee JK, Kim GH, Kim JS, Kim KK, Lee MC, Yoo HW. Identification of four novel mutations in five unrelated Korean families with Fabry disease. Clin Genet. 2000 Sep;58(3):228-33. PMID:11076046
- ↑ Ashton-Prolla P, Tong B, Shabbeer J, Astrin KH, Eng CM, Desnick RJ. Fabry disease: twenty-two novel mutations in the alpha-galactosidase A gene and genotype/phenotype correlations in severely and mildly affected hemizygotes and heterozygotes. J Investig Med. 2000 Jul;48(4):227-35. PMID:10916280
- ↑ Germain DP, Salard D, Fellmann F, Azibi K, Caillaud C, Bernard MC, Poenaru L. Identification of a novel de novo mutation (G373D) in the alpha-galactosidase A gene (GLA) in a patient affected with Fabry disease. Hum Mutat. 2001 Apr;17(4):353. PMID:11295840 doi:10.1002/humu.41
- ↑ Blaydon D, Hill J, Winchester B. Fabry disease: 20 novel GLA mutations in 35 families. Hum Mutat. 2001 Nov;18(5):459. PMID:11668641 doi:10.1002/humu.1219
- ↑ Branton MH, Schiffmann R, Sabnis SG, Murray GJ, Quirk JM, Altarescu G, Goldfarb L, Brady RO, Balow JE, Austin Iii HA, Kopp JB. Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course. Medicine (Baltimore). 2002 Mar;81(2):122-38. PMID:11889412
- ↑ Yang CC, Lai LW, Whitehair O, Hwu WL, Chiang SC, Lien YH. Two novel mutations in the alpha-galactosidase A gene in Chinese patients with Fabry disease. Clin Genet. 2003 Mar;63(3):205-9. PMID:12694230
- ↑ Lai LW, Whitehair O, Wu MJ, O'Meara M, Lien YH. Analysis of splice-site mutations of the alpha-galactosidase A gene in Fabry disease. Clin Genet. 2003 Jun;63(6):476-82. PMID:12786754
- ↑ Verovnik F, Benko D, Vujkovac B, Linthorst GE. Remarkable variability in renal disease in a large Slovenian family with Fabry disease. Eur J Hum Genet. 2004 Aug;12(8):678-81. PMID:15162124 doi:10.1038/sj.ejhg.5201184
- ↑ Shabbeer J, Robinson M, Desnick RJ. Detection of alpha-galactosidase a mutations causing Fabry disease by denaturing high performance liquid chromatography. Hum Mutat. 2005 Mar;25(3):299-305. PMID:15712228 doi:10.1002/humu.20144
- ↑ Nance CS, Klein CJ, Banikazemi M, Dikman SH, Phelps RG, McArthur JC, Rodriguez M, Desnick RJ. Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome. Arch Neurol. 2006 Mar;63(3):453-7. PMID:16533976 doi:63/3/453
- ↑ Hwu WL, Chien YH, Lee NC, Chiang SC, Dobrovolny R, Huang AC, Yeh HY, Chao MC, Lin SJ, Kitagawa T, Desnick RJ, Hsu LW. Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G>A (IVS4+919G>A). Hum Mutat. 2009 Oct;30(10):1397-405. doi: 10.1002/humu.21074. PMID:19621417 doi:10.1002/humu.21074
- ↑ Li HY, Lin HY, Chang SK, Chiu YT, Hou CC, Ko TP, Huang KF, Niu DM, Cheng WC. Mechanistic Insights into Dibasic Iminosugars as pH-Selective Pharmacological Chaperones to Stabilize Human α-Galactosidase. JACS Au. 2024 Feb 23;4(3):908-918. PMID:38559739 doi:10.1021/jacsau.3c00684
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