c7b206f0605bdae360fdbc4ce093e4a2 intjoumol_a2021v22n12p6518.pdf 633fe6693b5277951abe1a886666f9aa3069673c intjoumol_a2021v22n12p6518.pdf 8bb20e164260412c48f1c3d7c07dabf6a8df2f4ad1a54b3636010e5c1aad31cb intjoumol_a2021v22n12p6518.pdf Title: Human -Galactosidase A Mutants: Priceless Tools to Develop Novel Therapies for Fabry Disease Subject: Fabry disease (FD) is a lysosomal storage disease caused by mutations in the gene for the -galactosidase A (GLA) enzyme. The absence of the enzyme or its activity results in the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), in different tissues, leading to a wide range of clinical manifestations. More than 1000 natural variants have been described in the GLA gene, most of them affecting proper protein folding and enzymatic activity. Currently, FD is treated by enzyme replacement therapy (ERT) or pharmacological chaperone therapy (PCT). However, as both approaches show specific drawbacks, new strategies (such as new forms of ERT, organ/cell transplant, substrate reduction therapy, or gene therapy) are under extensive study. In this review, we summarize GLA mutants described so far and discuss their putative application for the development of novel drugs for the treatment of FD. Unfavorable mutants with lower activities and stabilities than wild-type enzymes could serve as tools for the development of new pharmacological chaperones. On the other hand, GLA mutants showing improved enzymatic activity have been identified and produced in vitro. Such mutants could overcome several complications associated with current ERT, as lower-dose infusions of these mutants could achieve a therapeutic effect equivalent to that of the wild-type enzyme. Keywords: alpha-galactosidase A; Fabry disease; pharmacological chaperones; rare diseases; enzyme replacement therapy Author: Andrea Modrego, Marilla Amaranto, Agustina Godino, Rosa Mendoza, José Luis Barra and José Luis Corchero Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Jun 21 03:43:16 2021 CEST ModDate: Thu Sep 16 18:42:31 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 17 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1277579 bytes Optimized: yes PDF version: 1.6 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ZYLSXN+URWPalladioL-Roma Type 1 Custom yes yes no 369 0 BTFGED+VnURWPalladioL-Bold Type 1 Custom yes yes no 370 0 QDCWHF+EURM10 Type 1 Builtin yes yes no 371 0 IHGURL+EURM7 Type 1 Builtin yes yes no 372 0 CZOINJ+EURB10 Type 1 Builtin yes yes no 373 0 MWHIBA+VnURWPalladioL Type 1 Custom yes yes no 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SignatureMatches: PDF-hul MIMEtype: application/pdf Profile: Linearized PDF PDFMetadata: Objects: 446 FreeObjects: 1 IncrementalUpdates: 1 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Fabry Disease Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: The Human Gla Enzyme Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Children: Item: Title: Structure of GLA Enzyme Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: GLA Synthesis and Trafficking Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: Catalytic Mechanism of GLA Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: Current Treatments For FD Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Children: Item: Title: Enzyme Replacement Therapy Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: Pharmacological Chaperones Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Item: Title: GLA Mutations Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Children: Item: Title: Most Frequent GLA Mutant Variants Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1060b431 Item: Title: Most Frequently Mutated Residues Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612679d6 Item: Title: Nonsense Mutations Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@11758f2a Item: Title: Location-Dependent Biological Effect of Mutations Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@e720b71 Item: Title: GLA Mutants with Low Activity and/or Stability Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1b26f7b2 Item: Title: GLA Mutants with Improved Activity and/or Stability Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@491cc5c9 Item: Title: Other Modifications in Recombinant GLAs in Innovative FD Therapies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@74ad1f1f Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6a1aab78 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@462d5aee Info: Title: Human -Galactosidase A Mutants: Priceless Tools to Develop Novel Therapies for Fabry Disease Author: Andrea Modrego, Marilla Amaranto, Agustina Godino, Rosa Mendoza, José Luis Barra and José Luis Corchero Subject: Fabry disease (FD) is a lysosomal storage disease caused by mutations in the gene for the -galactosidase A (GLA) enzyme. The absence of the enzyme or its activity results in the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), in different tissues, leading to a wide range of clinical manifestations. More than 1000 natural variants have been described in the GLA gene, most of them affecting proper protein folding and enzymatic activity. Currently, FD is treated by enzyme replacement therapy (ERT) or pharmacological chaperone therapy (PCT). However, as both approaches show specific drawbacks, new strategies (such as new forms of ERT, organ/cell transplant, substrate reduction therapy, or gene therapy) are under extensive study. In this review, we summarize GLA mutants described so far and discuss their putative application for the development of novel drugs for the treatment of FD. Unfavorable mutants with lower activities and stabilities than wild-type enzymes could serve as tools for the development of new pharmacological chaperones. On the other hand, GLA mutants showing improved enzymatic activity have been identified and produced in vitro. Such mutants could overcome several complications associated with current ERT, as lower-dose infusions of these mutants could achieve a therapeutic effect equivalent to that of the wild-type enzyme. Keywords: alpha-galactosidase A; Fabry disease; pharmacological chaperones; rare diseases; enzyme replacement therapy Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Jun 21 03:43:16 CEST 2021 ModDate: Thu Sep 16 18:42:31 CEST 2021 ID: 0xf6c27d37371734609e11ce1502cfa166, 0xd633d62da246b64b92c87eec26ffed6f Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: ZYLSXN+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 248 FontDescriptor: FontName: ZYLSXN+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: BTFGED+VnURWPalladioL-Bold FontSubset: true FirstChar: 178 LastChar: 178 FontDescriptor: FontName: BTFGED+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: QDCWHF+EURM10 FontSubset: true FirstChar: 11 LastChar: 12 FontDescriptor: FontName: QDCWHF+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: IHGURL+EURM7 FontSubset: true FirstChar: 11 LastChar: 11 FontDescriptor: FontName: IHGURL+EURM7 Flags: Symbolic FontBBox: -5, -243, 1229, 720 FontFile: true Font: BaseFont: MPUDFL+PazoMath FontSubset: true FirstChar: 68 LastChar: 68 FontDescriptor: FontName: MPUDFL+PazoMath Flags: Symbolic FontBBox: -40, -283, 878, 946 FontFile: true Font: BaseFont: CZOINJ+EURB10 FontSubset: true FirstChar: 11 LastChar: 11 FontDescriptor: FontName: CZOINJ+EURB10 Flags: Symbolic FontBBox: -30, -247, 1178, 723 FontFile: true Font: BaseFont: MWHIBA+VnURWPalladioL FontSubset: true FirstChar: 161 LastChar: 226 FontDescriptor: FontName: MWHIBA+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: PYRJTD+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 174 FontDescriptor: FontName: PYRJTD+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: QGUKZH+CMSY10 FontSubset: true FirstChar: 14 LastChar: 14 FontDescriptor: FontName: QGUKZH+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Font: BaseFont: OJVOYB+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: OJVOYB+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true XMP: 2021-06-21T09:43:16+08:00 LaTeX with hyperref 2021-09-16T18:42:31+02:00 2021-09-16T18:42:31+02:00 application/pdf Fabry disease (FD) is a lysosomal storage disease caused by mutations in the gene for the -galactosidase A (GLA) enzyme. The absence of the enzyme or its activity results in the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), in different tissues, leading to a wide range of clinical manifestations. More than 1000 natural variants have been described in the GLA gene, most of them affecting proper protein folding and enzymatic activity. Currently, FD is treated by enzyme replacement therapy (ERT) or pharmacological chaperone therapy (PCT). However, as both approaches show specific drawbacks, new strategies (such as new forms of ERT, organ/cell transplant, substrate reduction therapy, or gene therapy) are under extensive study. In this review, we summarize GLA mutants described so far and discuss their putative application for the development of novel drugs for the treatment of FD. Unfavorable mutants with lower activities and stabilities than wild-type enzymes could serve as tools for the development of new pharmacological chaperones. On the other hand, GLA mutants showing improved enzymatic activity have been identified and produced in vitro. Such mutants could overcome several complications associated with current ERT, as lower-dose infusions of these mutants could achieve a therapeutic effect equivalent to that of the wild-type enzyme. 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