module: dmel_glycosaminoglycan_biosynthesis title: Heparan sulfate and chondroitin sulfate proteoglycan biosynthesis in Drosophila melanogaster label: Glycosaminoglycan biosynthesis module_type: METABOLIC_PATHWAY description: >- Heparan sulfate and chondroitin sulfate chains are built in the endoplasmic reticulum and Golgi on serine residues of core proteins such as the glypicans Dally and Dally-like, Syndecan and Perlecan. Both start on a shared tetrasaccharide linker (xylose-galactose-galactose-glucuronic acid) made by Oxt, beta4GalT7, beta3GalTII and GlcAT-I. Addition of N-acetylglucosamine by Brother of tout-velu (Botv) commits the chain to heparan sulfate; the Tout-velu (Ttv) and Sister of tout-velu (Sotv) exostosin complex then polymerizes alternating glucuronic acid and N-acetylglucosamine. The chain is modified by the N-deacetylase/N-sulfotransferase Sulfateless (Sfl), the C5-epimerase Hsepi and the 2-O-, 6-O- and 3-O-sulfotransferases (Hs2st, Hs6st, Hs3st-A, Hs3st-B). Addition of N-acetylgalactosamine by Csgalnact instead starts chondroitin chains, which are polymerized by Chsy and Chpf and sulfated by C4st. Heparan sulfate made by this pathway is required for Wingless, Hedgehog, Dpp and FGF signaling in Drosophila. summary: >- Linker tetrasaccharide synthesis, then heparan sulfate (Botv, Ttv-Sotv, Sfl, Hsepi, sulfotransferases) or chondroitin sulfate (Csgalnact, Chsy, Chpf, C4st) chain synthesis and modification. concepts: - {id: GO:0006024, label: glycosaminoglycan biosynthetic process} - {id: GO:0015012, label: heparan sulfate proteoglycan biosynthetic process} - {id: GO:0050650, label: chondroitin sulfate proteoglycan biosynthetic process} cellular_components: - {id: GO:0005794, label: Golgi apparatus} parts: - id: linker_tetrasaccharide label: Linker tetrasaccharide synthesis role: shared xylose-galactose-galactose-glucuronic acid linker processes: - {id: GO:0120532, label: glycosaminoglycan-protein linkage region biosynthetic process} parts: - id: xylosylation label: Core protein xylosylation role: xylose transfer to core-protein serine genes: [Oxt] function: {id: GO:0030158, label: protein xylosyltransferase activity} - id: first_galactosylation label: First galactose addition role: galactose addition to xylose genes: [beta4GalT7] function: {id: GO:0046525, label: xylosylprotein 4-beta-galactosyltransferase activity} - id: second_galactosylation label: Second galactose addition role: galactose addition to galactose-xylose genes: [beta3GalTII] - id: linker_glucuronylation label: Linker glucuronic acid addition role: glucuronic acid addition completing the linker genes: [GlcAT-I] function: {id: GO:0015018, label: galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase activity} connections: - {source: xylosylation, target: first_galactosylation, connection_type: PRECEDES, description: Xylosylated core protein is galactosylated.} - {source: first_galactosylation, target: second_galactosylation, connection_type: PRECEDES, description: A second galactose is added.} - {source: second_galactosylation, target: linker_glucuronylation, connection_type: PRECEDES, description: Glucuronic acid completes the linker.} - id: heparan_sulfate_chain label: Heparan sulfate chain synthesis and modification role: heparan sulfate initiation, polymerization and modification processes: - {id: GO:0015012, label: heparan sulfate proteoglycan biosynthetic process} parts: - id: hs_initiation label: Heparan sulfate chain initiation role: first N-acetylglucosamine addition to the linker genes: [botv] function: {id: GO:0001888, label: glucuronyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity} - id: hs_polymerization label: Heparan sulfate polymerization role: alternating glucuronic acid and N-acetylglucosamine polymerization description: Tout-velu and Sister of tout-velu act together as the heparan sulfate copolymerase. genes: [ttv, sotv] module_type: PROTEIN_COMPLEX complex: true complex_term: {id: GO:0120504, label: EXT1-EXT2 complex} - id: hs_n_sulfation label: N-deacetylation and N-sulfation role: N-deacetylation and N-sulfation of glucosamine genes: [sfl] function: {id: GO:0015016, label: heparan sulfate N-sulfotransferase activity} - id: hs_epimerization label: Glucuronic acid C5 epimerization role: glucuronic acid to iduronic acid genes: [Hsepi] function: {id: GO:0047464, label: heparosan-N-sulfate-glucuronate 5-epimerase activity} - id: hs_2_o_sulfation label: 2-O-sulfation role: uronic acid 2-O-sulfation genes: [Hs2st] function: {id: GO:0004394, label: heparan sulfate 2-sulfotransferase activity} - id: hs_6_o_sulfation label: 6-O-sulfation role: glucosamine 6-O-sulfation genes: [Hs6st] function: {id: GO:0017095, label: heparan sulfate 6-sulfotransferase activity} - id: hs_3_o_sulfation label: 3-O-sulfation role: glucosamine 3-O-sulfation genes: [Hs3st-A, Hs3st-B] complex: false function: {id: GO:0008467, label: "[heparan sulfate]-glucosamine 3-sulfotransferase activity"} connections: - {source: hs_initiation, target: hs_polymerization, connection_type: PRECEDES, description: The primed linker is elongated by Ttv-Sotv.} - {source: hs_polymerization, target: hs_n_sulfation, connection_type: PRECEDES, description: The nascent chain is N-deacetylated and N-sulfated by Sfl.} - {source: hs_n_sulfation, target: hs_epimerization, connection_type: PRECEDES, description: N-sulfated regions are epimerized by Hsepi.} - {source: hs_epimerization, target: hs_2_o_sulfation, connection_type: PRECEDES, description: Iduronic acid residues are 2-O-sulfated.} - {source: hs_n_sulfation, target: hs_6_o_sulfation, connection_type: PRECEDES, description: N-sulfated glucosamine residues are 6-O-sulfated.} - {source: hs_n_sulfation, target: hs_3_o_sulfation, connection_type: PRECEDES, description: N-sulfated glucosamine residues can be 3-O-sulfated.} - id: chondroitin_sulfate_chain label: Chondroitin sulfate chain synthesis and modification role: chondroitin initiation, polymerization and sulfation processes: - {id: GO:0050650, label: chondroitin sulfate proteoglycan biosynthetic process} parts: - id: cs_initiation label: Chondroitin chain initiation role: first N-acetylgalactosamine addition to the linker genes: [Csgalnact] - id: cs_polymerization label: Chondroitin polymerization role: alternating glucuronic acid and N-acetylgalactosamine polymerization genes: [Chsy, Chpf] complex: false - id: cs_4_o_sulfation label: Chondroitin 4-O-sulfation role: N-acetylgalactosamine 4-O-sulfation genes: [C4st] connections: - {source: cs_initiation, target: cs_polymerization, connection_type: PRECEDES, description: The primed linker is elongated by Chsy and Chpf.} - {source: cs_polymerization, target: cs_4_o_sulfation, connection_type: PRECEDES, description: The chondroitin chain is 4-O-sulfated.} connections: - source: linker_tetrasaccharide target: heparan_sulfate_chain connection_type: PRECEDES description: The completed linker is primed for heparan sulfate by Botv. - source: linker_tetrasaccharide target: chondroitin_sulfate_chain connection_type: PRECEDES description: The completed linker is primed for chondroitin by Csgalnact. notes: >- Boundary. The module joins three FlyBase groups: heparan sulfate proteoglycan biosynthesis (GAHSB), chondroitin sulfate proteoglycan biosynthesis (GACSB) and the EXT1-EXT2 complex. Core proteins, the PAPS synthesis and transport machinery (Papss, Papst1, Papst2), UDP-sugar transporters and the extracellular 6-O-endosulfatase Sulf1 are not parts. Molecular functions are assigned where the fly enzyme or its well-studied ortholog has an established activity; beta3GalTII, Csgalnact, Chsy, Chpf and C4st and the Ttv-Sotv complex are left without a function term (the copolymerase has two activities that no single GO term captures). groups: [GAHSB, GACSB, EXT1-EXT2]