基于合成生物学策略实现糖胺聚糖的微生物合成
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摘要
糖胺聚糖广泛应用于化妆品和保健品领域以及血栓、骨关节炎、癌症等临床医疗.目前,商品化糖胺聚糖依赖于动物组织提取,产品存在均一性差、有潜在致病因子等缺点.采用合成生物学策略合成糖胺聚糖及其寡糖可避免上述问题,且可实现精准控制硫酸化程度及产品分子量分布.随着基因组学和合成生物学的发展,透明质酸、软骨素、肝素前体、硫酸软骨素及肝素等的合成途径被阐释,多种平台菌株的遗传操作体系不断完善.基于合成生物学策略构建微生物细胞工厂合成糖胺聚糖已成为未来发展趋势.本文主要综述了近年来生产糖胺聚糖及其寡聚糖的生物策略尤其是相关合成生物学手段,以期为未来研究提供新思路.
Glycosaminoglycans(GAGs) are widely used in cosmetics, health care and clinical treatments of thrombosis, osteoarthritis and cancer. Commercial GAGs largely depend on extraction from animal tissues. However, the products have poor homogeneity and carry potential pathogenic factors. Synthetic biology strategies for production GAGs and its oligosaccharides can avoid the above problems,and achieve precise control of the sulfation degree and molecular weights of GAG. With the development of genomics and synthetic biology, the biosynthesis pathways of hyaluronan, chondroitin, heparin, chondroitin sulfate and heparin have been elucidated, and many genetic operation systems for platform strains have also been continuously improved. Construction of microbial cell factories for producing GAGs has been considered as main development trends. This review summarized and discussed the recent biological strategies for the production of GAGs and their oligosaccharides, and provided new ideas for near future studies.
Glycosaminoglycans(GAGs) are widely used in cosmetics, health care and clinical treatments of thrombosis, osteoarthritis and cancer. Commercial GAGs largely depend on extraction from animal tissues. However, the products have poor homogeneity and carry potential pathogenic factors. Synthetic biology strategies for production GAGs and its oligosaccharides can avoid the above problems,and achieve precise control of the sulfation degree and molecular weights of GAG. With the development of genomics and synthetic biology, the biosynthesis pathways of hyaluronan, chondroitin, heparin, chondroitin sulfate and heparin have been elucidated, and many genetic operation systems for platform strains have also been continuously improved. Construction of microbial cell factories for producing GAGs has been considered as main development trends. This review summarized and discussed the recent biological strategies for the production of GAGs and their oligosaccharides, and provided new ideas for near future studies.
引文
1 da Costa D S,Reis R L,Pashkuleva I.Sulfation of glycosaminoglycans and its implications in human health and disorders.Annu Rev Biomed Eng,2017,19:1-26
2 Vaidyanathan D,Williams A,Dordick J S,et al.Engineered heparins as new anticoagulant drugs.Bioeng Transl Med,2017,2:17-30
3 Chen Q,Shao X,Ling P,et al.Recent advances in polysaccharides for osteoarthritis therapy.Eur J Med Chem,2017,139:926-935
4 Ruffell B,Poon G F T,Lee S S M,et al.Differential use of chondroitin sulfate to regulate hyaluronan binding by receptor CD44 in inflammatory and interleukin 4-activated macrophages.J Biol Chem,2011,286:19179-19190
5 Salwowska N M,Bebenek K A,??d?o D A,et al.Physiochemical properties and application of hyaluronic acid:A systematic review.J Cosmet Dermatol,2016,15:520-526
6 Yan Y,Ji Y,Su N,et al.Non-anticoagulant effects of low molecular weight heparins in inflammatory disorders:A review.Carbohydr Polym,2017,160:71-81
7 Stern R,Asari A A,Sugahara K N.Hyaluronan fragments:An information-rich system.Eur J Cell Biol,2006,85:699-715
8 Soltés L,Kogan G,Stankovska M,et al.Degradation of high-molar-mass hyaluronan and characterization of fragments.Biomacromolecules,2007,8:2697-2705
9 Collins M N,Birkinshaw C.Hyaluronic acid based scaffolds for tissue engineering-A review.Carbohydr Polym,2013,92:1262-1279
10 Barzu T,Lormeau J C,Petitou M,et al.Heparin-derived oligosaccharides:Affinity for acidic fibroblast growth factor and effect on its growthpromoting activity for human endothelial cells.J Cell Physiol,1989,140:538-548
11 Pan J,Qian Y,Zhou X,et al.Oversulfated chondroitin sulfate is not the sole contaminant in heparin.Nat Biotechnol,2010,28:203-207
12 Shi Y,Meng Y,Li J,et al.Chondroitin sulfate:Extraction,purification,microbial and chemical synthesis.J Chem Technol Biotechnol,2014,89:1445-1465
13 Bedini E,Parrilli M.Synthetic and semi-synthetic chondroitin sulfate oligosaccharides,polysaccharides,and glycomimetics.Carbohydr Res,2012,356:75-85
14 Mende M,Bednarek C,Wawryszyn M,et al.Chemical synthesis of glycosaminoglycans.Chem Rev,2016,116:8193-8255
15 Boltje T J,Buskas T,Boons G J.Opportunities and challenges in synthetic oligosaccharide and glycoconjugate research.Nat Chem,2009,1:611-622
16 Chavaroche A A E,van den Broek L A M,Eggink G.Production methods for heparosan,a precursor of heparin and heparan sulfate.Carbohydr Polym,2013,93:38-47
17 Cimini D,De Rosa M,Carlino E,et al.Homologous overexpression of rfaH in E.coli K4 improves the production of chondroitin-like capsular polysaccharide.Microb Cell Fact,2013,12:46
18 Jin P,Zhang L,Yuan P,et al.Efficient biosynthesis of polysaccharides chondroitin and heparosan by metabolically engineered Bacillus subtilis.Carbohydr Polym,2016,140:424-432
19 He W,Fu L,Li G,et al.Production of chondroitin in metabolically engineered E.coli.Metabo Eng,2015,27:92-100
20 Jeong E,Shim W Y,Kim J H.Metabolic engineering of Pichia pastoris for production of hyaluronic acid with high molecular weight.J Biotech,2014,185:28-36
21 Chen X,Chen R,Yu X,et al.Metabolic engineering of Bacillus subtilis for biosynthesis of heparosan using heparosan synthase from Pasteurella multocida,PmHS1.Bioproc Biosyst Eng,2017,40:675-681
22 Zhang Q,Yao R,Chen X,et al.Enhancing fructosylated chondroitin production in Escherichia coli K4 by balancing the UDP-precursors.Metabol Eng,2018,47:314-322
23 Zhou Z,Li Q,Huang H,et al.A microbial-enzymatic strategy for producing chondroitin sulfate glycosaminoglycans.Biotechnol Bioeng,2018,115:1561-1570
24 Li Y J,Yin F X,Zhang X K,et al.Characterization of heparan sulfate N-deacetylase/N-sulfotransferase isoform 4 using synthetic oligosaccharide substrates.Biochim Biophys Acta,2018,1862:547-556
25 He W,Zhu Y,Shirke A,et al.Expression of chondroitin-4-O-sulfotransferase in Escherichia coli and Pichia pastoris.Appl Microbiol Biotech,2017,101:6919-6928
26 Yuan P,Lv M,Jin P,et al.Enzymatic production of specifically distributed hyaluronan oligosaccharides.Carbohydr Polym,2015,129:194-200
27 Su G,Li L,Huang H,et al.Production of a low molecular weight heparin production using recombinant glycuronidase.Carbohydr Polym,2015,134:151-157
28 Gibson D G,Young L,Chuang R Y,et al.Enzymatic assembly of DNA molecules up to several hundred kilobases.Nat Methods,2009,6:343-345
29 Mercy G,Mozziconacci J,Scolari V F,et al.3D organization of synthetic and scrambled chromosomes.Science,2017,355:eaaf4597
30 Jin P,Ding W,Du G,et al.DATEL:A scarless and sequence-independent DNA assembly method using thermostable exonucleases and ligase.ACS Synth Biol,2016,5:1028-1032
31 Cameron D E,Bashor C J,Collins J J.A brief history of synthetic biology.Nat Rev Micro,2014,12:381-390
32 Liu L,Liu Y,Li J,et al.Microbial production of hyaluronic acid:Current state,challenges,and perspectives.Microb Cell Fact,2011,10:99
33 de Oliveira J D,Carvalho L S,Gomes A M V,et al.Genetic basis for hyper production of hyaluronic acid in natural and engineered microorganisms.Microb Cell Fact,2016,15:119
34 Chong B F,Blank L M,Mclaughlin R,et al.Microbial hyaluronic acid production.Appl Microbiol Biotech,2005,66:341-351
35 Weigel P H,DeAngelis P L.Hyaluronan synthases:A decade-plus of novel glycosyltransferases.J Biol Chem,2007,282:36777-36781
36 Hubbard C,McNamara J T,Azumaya C,et al.The hyaluronan synthase catalyzes the synthesis and membrane translocation of hyaluronan.J Mol Biol,2012,418:21-31
37 Jin P,Kang Z,Zhang J,et al.Combinatorial evolution of enzymes and synthetic pathways using one-step PCR.ACS Synth Biol,2016,5:259-268
38 Zhang L,Huang H,Wang H,et al.Rapid evolution of hyaluronan synthase to improve hyaluronan production and molecular mass in Bacillus subtilis.Biotech Lett,2016,38:2103-2108
39 Badle S S,Jayaraman G,Ramachandran K B.Ratio of intracellular precursors concentration and their flux influences hyaluronic acid molecular weight in Streptococcus zooepidemicus and recombinant Lactococcus lactis.Bioresour Tech,2014,163:222-227
40 Sheng J,Ling P,Wang F.Constructing a recombinant hyaluronic acid biosynthesis operon and producing food-grade hyaluronic acid in Lactococcus lactis.J Ind Microbiol Biotech,2015,42:197-206
41 Cheng F,Luozhong S,Guo Z,et al.Enhanced biosynthesis of hyaluronic acid using engineered Corynebacterium glutamicum via metabolic pathway regulation.Biotech J,2017,12:1700191
42 Jin P,Kang Z,Yuan P,et al.Production of specific-molecular-weight hyaluronan by metabolically engineered Bacillus subtilis 168.Metabol Eng,2016,35:21-30
43 Smirnou D,Kr?má?M,Kulhánek J,et al.Characterization of hyaluronan-degrading enzymes from yeasts.Appl Biochem Biotech,2015,177:700-712
44 Bakke M,Kamei J,Obata A.Identification,characterization,and molecular cloning of a novel hyaluronidase,a member of glycosyl hydrolase family 16,from Penicillium spp.FEBS Lett,2011,585:115-120
45 Guo X,Shi Y,Sheng J,et al.A novel hyaluronidase produced by Bacillus sp.A50.PLoS ONE,2014,9:e94156
46 Jin P,Kang Z,Zhang N,et al.High-yield novel leech hyaluronidase to expedite the preparation of specific hyaluronan oligomers.Sci Rep,2014,4:4471
47 Kang Z,Zhang N,Zhang Y.Enhanced production of leech hyaluronidase by optimizing secretion and cultivation in Pichia pastoris.Appl Microbiol Biotech,2016,100:707-717
48 Cimini D,Carlino E,Giovane A,et al.Engineering a branch of the UDP-precursor biosynthesis pathway enhances the production of capsular polysaccharide in Escherichia coli O5:K4:H4.Biotech J,2015,10:1307-1315
49 Huang H,Liu X,Lv S,et al.Recombinant Escherichia coli K5 strain with the deletion of waaR gene decreases the molecular weight of the heparosan capsular polysaccharide.Appl Microbiol Biotech,2016,100:7877-7885
50 Hickey A M,Bhaskar U,Linhardt R J,et al.Effect of eliminase gene(elmA)deletion on heparosan production and shedding in Escherichia coli K5.J Biotech,2013,165:175-177
51 Yu H,Stephanopoulos G.Metabolic engineering of Escherichia coli for biosynthesis of hyaluronic acid.Metabol Eng,2008,10:24-32
52 Widner B,Behr R,Von Dollen S,et al.Hyaluronic acid production in Bacillus subtilis.Appl Environ Microbiol,2005,71:3747-3752
53 Douglas T,Heinemann S,Mietrach C,et al.Interactions of collagen types I and II with chondroitin sulfates A-C and their effect on osteoblast adhesion.Biomacromolecules,2007,8:1085-1092
54 McAlindon T E,LaValley M P,Gulin J P,et al.Glucosamine and chondroitin for treatment of osteoarthritis.JAMA,2000,283:1469-1475
55 Bedini E,De Castro C,De Rosa M,et al.A microbiological-chemical strategy to produce chondroitin sulfate A,C.Angew Chem Int Ed,2011,50:6160-6163
56 Hemker H C.A century of heparin:Past,present and future.J Thromb Haemost,2016,14:2329-2338
57 Oduah E I,Linhardt R J,Sharfstein S T.Heparin:Past,present,and future.Pharmaceuticals,2016,9:38
58 Suflita M,Fu L,He W,et al.Heparin and related polysaccharides:Synthesis using recombinant enzymes and metabolic engineering.Appl Microbiol Biotech,2015,99:7465-7479
59 Fu L,Suflita M,Linhardt R J.Bioengineered heparins and heparan sulfates.Adv Drug Deliv Rev,2016,97:237-249
60 Sariba?A S,Mobasseri A,Pristatsky P,et al.Production of N-sulfated polysaccharides using yeast-expressed N-deacetylase/N-sulfotransferase-1(NDST-1).Glycobiology,2004,14:1217-1228
61 Englaender J A,Zhu Y,Shirke A N,et al.Expression and secretion of glycosylated heparin biosynthetic enzymes using Komagataella pastoris.Appl Microbiol Biotech,2017,101:2843-2851
62 Zhang J,Suflita M,Li G,et al.High cell density cultivation of recombinant Escherichia coli strains expressing 2-O-sulfotransferase and C5-epimerase for the production of bioengineered heparin.Appl Biochem Biotech,2015,175:2986-2995
63 Zhou X,O’Leary T R,Xu Y,et al.Chemoenzymatic synthesis of heparan sulfate and heparin.Biocatal Biotransform,2012,30:296-308
64 Kang Z,Zhou Z,Wang Y,et al.Bio-based strategies for producing glycosaminoglycans and their oligosaccharides.Trends Biotech,2018,36:806-818
65 Funderburgh J L.MINI REVIEW Keratan sulfate:Structure,biosynthesis,and function.Glycobiology,2000,10:951-958
66 Caterson B,Melrose J.Keratan sulfate,a complex glycosaminoglycan with unique functional capability.Glycobiology,2018,28:182-206
67 Pomin V H.Keratan sulfate:An up-to-date review.Int J Biol Macromolecules,2015,72:282-289
2 Vaidyanathan D,Williams A,Dordick J S,et al.Engineered heparins as new anticoagulant drugs.Bioeng Transl Med,2017,2:17-30
3 Chen Q,Shao X,Ling P,et al.Recent advances in polysaccharides for osteoarthritis therapy.Eur J Med Chem,2017,139:926-935
4 Ruffell B,Poon G F T,Lee S S M,et al.Differential use of chondroitin sulfate to regulate hyaluronan binding by receptor CD44 in inflammatory and interleukin 4-activated macrophages.J Biol Chem,2011,286:19179-19190
5 Salwowska N M,Bebenek K A,??d?o D A,et al.Physiochemical properties and application of hyaluronic acid:A systematic review.J Cosmet Dermatol,2016,15:520-526
6 Yan Y,Ji Y,Su N,et al.Non-anticoagulant effects of low molecular weight heparins in inflammatory disorders:A review.Carbohydr Polym,2017,160:71-81
7 Stern R,Asari A A,Sugahara K N.Hyaluronan fragments:An information-rich system.Eur J Cell Biol,2006,85:699-715
8 Soltés L,Kogan G,Stankovska M,et al.Degradation of high-molar-mass hyaluronan and characterization of fragments.Biomacromolecules,2007,8:2697-2705
9 Collins M N,Birkinshaw C.Hyaluronic acid based scaffolds for tissue engineering-A review.Carbohydr Polym,2013,92:1262-1279
10 Barzu T,Lormeau J C,Petitou M,et al.Heparin-derived oligosaccharides:Affinity for acidic fibroblast growth factor and effect on its growthpromoting activity for human endothelial cells.J Cell Physiol,1989,140:538-548
11 Pan J,Qian Y,Zhou X,et al.Oversulfated chondroitin sulfate is not the sole contaminant in heparin.Nat Biotechnol,2010,28:203-207
12 Shi Y,Meng Y,Li J,et al.Chondroitin sulfate:Extraction,purification,microbial and chemical synthesis.J Chem Technol Biotechnol,2014,89:1445-1465
13 Bedini E,Parrilli M.Synthetic and semi-synthetic chondroitin sulfate oligosaccharides,polysaccharides,and glycomimetics.Carbohydr Res,2012,356:75-85
14 Mende M,Bednarek C,Wawryszyn M,et al.Chemical synthesis of glycosaminoglycans.Chem Rev,2016,116:8193-8255
15 Boltje T J,Buskas T,Boons G J.Opportunities and challenges in synthetic oligosaccharide and glycoconjugate research.Nat Chem,2009,1:611-622
16 Chavaroche A A E,van den Broek L A M,Eggink G.Production methods for heparosan,a precursor of heparin and heparan sulfate.Carbohydr Polym,2013,93:38-47
17 Cimini D,De Rosa M,Carlino E,et al.Homologous overexpression of rfaH in E.coli K4 improves the production of chondroitin-like capsular polysaccharide.Microb Cell Fact,2013,12:46
18 Jin P,Zhang L,Yuan P,et al.Efficient biosynthesis of polysaccharides chondroitin and heparosan by metabolically engineered Bacillus subtilis.Carbohydr Polym,2016,140:424-432
19 He W,Fu L,Li G,et al.Production of chondroitin in metabolically engineered E.coli.Metabo Eng,2015,27:92-100
20 Jeong E,Shim W Y,Kim J H.Metabolic engineering of Pichia pastoris for production of hyaluronic acid with high molecular weight.J Biotech,2014,185:28-36
21 Chen X,Chen R,Yu X,et al.Metabolic engineering of Bacillus subtilis for biosynthesis of heparosan using heparosan synthase from Pasteurella multocida,PmHS1.Bioproc Biosyst Eng,2017,40:675-681
22 Zhang Q,Yao R,Chen X,et al.Enhancing fructosylated chondroitin production in Escherichia coli K4 by balancing the UDP-precursors.Metabol Eng,2018,47:314-322
23 Zhou Z,Li Q,Huang H,et al.A microbial-enzymatic strategy for producing chondroitin sulfate glycosaminoglycans.Biotechnol Bioeng,2018,115:1561-1570
24 Li Y J,Yin F X,Zhang X K,et al.Characterization of heparan sulfate N-deacetylase/N-sulfotransferase isoform 4 using synthetic oligosaccharide substrates.Biochim Biophys Acta,2018,1862:547-556
25 He W,Zhu Y,Shirke A,et al.Expression of chondroitin-4-O-sulfotransferase in Escherichia coli and Pichia pastoris.Appl Microbiol Biotech,2017,101:6919-6928
26 Yuan P,Lv M,Jin P,et al.Enzymatic production of specifically distributed hyaluronan oligosaccharides.Carbohydr Polym,2015,129:194-200
27 Su G,Li L,Huang H,et al.Production of a low molecular weight heparin production using recombinant glycuronidase.Carbohydr Polym,2015,134:151-157
28 Gibson D G,Young L,Chuang R Y,et al.Enzymatic assembly of DNA molecules up to several hundred kilobases.Nat Methods,2009,6:343-345
29 Mercy G,Mozziconacci J,Scolari V F,et al.3D organization of synthetic and scrambled chromosomes.Science,2017,355:eaaf4597
30 Jin P,Ding W,Du G,et al.DATEL:A scarless and sequence-independent DNA assembly method using thermostable exonucleases and ligase.ACS Synth Biol,2016,5:1028-1032
31 Cameron D E,Bashor C J,Collins J J.A brief history of synthetic biology.Nat Rev Micro,2014,12:381-390
32 Liu L,Liu Y,Li J,et al.Microbial production of hyaluronic acid:Current state,challenges,and perspectives.Microb Cell Fact,2011,10:99
33 de Oliveira J D,Carvalho L S,Gomes A M V,et al.Genetic basis for hyper production of hyaluronic acid in natural and engineered microorganisms.Microb Cell Fact,2016,15:119
34 Chong B F,Blank L M,Mclaughlin R,et al.Microbial hyaluronic acid production.Appl Microbiol Biotech,2005,66:341-351
35 Weigel P H,DeAngelis P L.Hyaluronan synthases:A decade-plus of novel glycosyltransferases.J Biol Chem,2007,282:36777-36781
36 Hubbard C,McNamara J T,Azumaya C,et al.The hyaluronan synthase catalyzes the synthesis and membrane translocation of hyaluronan.J Mol Biol,2012,418:21-31
37 Jin P,Kang Z,Zhang J,et al.Combinatorial evolution of enzymes and synthetic pathways using one-step PCR.ACS Synth Biol,2016,5:259-268
38 Zhang L,Huang H,Wang H,et al.Rapid evolution of hyaluronan synthase to improve hyaluronan production and molecular mass in Bacillus subtilis.Biotech Lett,2016,38:2103-2108
39 Badle S S,Jayaraman G,Ramachandran K B.Ratio of intracellular precursors concentration and their flux influences hyaluronic acid molecular weight in Streptococcus zooepidemicus and recombinant Lactococcus lactis.Bioresour Tech,2014,163:222-227
40 Sheng J,Ling P,Wang F.Constructing a recombinant hyaluronic acid biosynthesis operon and producing food-grade hyaluronic acid in Lactococcus lactis.J Ind Microbiol Biotech,2015,42:197-206
41 Cheng F,Luozhong S,Guo Z,et al.Enhanced biosynthesis of hyaluronic acid using engineered Corynebacterium glutamicum via metabolic pathway regulation.Biotech J,2017,12:1700191
42 Jin P,Kang Z,Yuan P,et al.Production of specific-molecular-weight hyaluronan by metabolically engineered Bacillus subtilis 168.Metabol Eng,2016,35:21-30
43 Smirnou D,Kr?má?M,Kulhánek J,et al.Characterization of hyaluronan-degrading enzymes from yeasts.Appl Biochem Biotech,2015,177:700-712
44 Bakke M,Kamei J,Obata A.Identification,characterization,and molecular cloning of a novel hyaluronidase,a member of glycosyl hydrolase family 16,from Penicillium spp.FEBS Lett,2011,585:115-120
45 Guo X,Shi Y,Sheng J,et al.A novel hyaluronidase produced by Bacillus sp.A50.PLoS ONE,2014,9:e94156
46 Jin P,Kang Z,Zhang N,et al.High-yield novel leech hyaluronidase to expedite the preparation of specific hyaluronan oligomers.Sci Rep,2014,4:4471
47 Kang Z,Zhang N,Zhang Y.Enhanced production of leech hyaluronidase by optimizing secretion and cultivation in Pichia pastoris.Appl Microbiol Biotech,2016,100:707-717
48 Cimini D,Carlino E,Giovane A,et al.Engineering a branch of the UDP-precursor biosynthesis pathway enhances the production of capsular polysaccharide in Escherichia coli O5:K4:H4.Biotech J,2015,10:1307-1315
49 Huang H,Liu X,Lv S,et al.Recombinant Escherichia coli K5 strain with the deletion of waaR gene decreases the molecular weight of the heparosan capsular polysaccharide.Appl Microbiol Biotech,2016,100:7877-7885
50 Hickey A M,Bhaskar U,Linhardt R J,et al.Effect of eliminase gene(elmA)deletion on heparosan production and shedding in Escherichia coli K5.J Biotech,2013,165:175-177
51 Yu H,Stephanopoulos G.Metabolic engineering of Escherichia coli for biosynthesis of hyaluronic acid.Metabol Eng,2008,10:24-32
52 Widner B,Behr R,Von Dollen S,et al.Hyaluronic acid production in Bacillus subtilis.Appl Environ Microbiol,2005,71:3747-3752
53 Douglas T,Heinemann S,Mietrach C,et al.Interactions of collagen types I and II with chondroitin sulfates A-C and their effect on osteoblast adhesion.Biomacromolecules,2007,8:1085-1092
54 McAlindon T E,LaValley M P,Gulin J P,et al.Glucosamine and chondroitin for treatment of osteoarthritis.JAMA,2000,283:1469-1475
55 Bedini E,De Castro C,De Rosa M,et al.A microbiological-chemical strategy to produce chondroitin sulfate A,C.Angew Chem Int Ed,2011,50:6160-6163
56 Hemker H C.A century of heparin:Past,present and future.J Thromb Haemost,2016,14:2329-2338
57 Oduah E I,Linhardt R J,Sharfstein S T.Heparin:Past,present,and future.Pharmaceuticals,2016,9:38
58 Suflita M,Fu L,He W,et al.Heparin and related polysaccharides:Synthesis using recombinant enzymes and metabolic engineering.Appl Microbiol Biotech,2015,99:7465-7479
59 Fu L,Suflita M,Linhardt R J.Bioengineered heparins and heparan sulfates.Adv Drug Deliv Rev,2016,97:237-249
60 Sariba?A S,Mobasseri A,Pristatsky P,et al.Production of N-sulfated polysaccharides using yeast-expressed N-deacetylase/N-sulfotransferase-1(NDST-1).Glycobiology,2004,14:1217-1228
61 Englaender J A,Zhu Y,Shirke A N,et al.Expression and secretion of glycosylated heparin biosynthetic enzymes using Komagataella pastoris.Appl Microbiol Biotech,2017,101:2843-2851
62 Zhang J,Suflita M,Li G,et al.High cell density cultivation of recombinant Escherichia coli strains expressing 2-O-sulfotransferase and C5-epimerase for the production of bioengineered heparin.Appl Biochem Biotech,2015,175:2986-2995
63 Zhou X,O’Leary T R,Xu Y,et al.Chemoenzymatic synthesis of heparan sulfate and heparin.Biocatal Biotransform,2012,30:296-308
64 Kang Z,Zhou Z,Wang Y,et al.Bio-based strategies for producing glycosaminoglycans and their oligosaccharides.Trends Biotech,2018,36:806-818
65 Funderburgh J L.MINI REVIEW Keratan sulfate:Structure,biosynthesis,and function.Glycobiology,2000,10:951-958
66 Caterson B,Melrose J.Keratan sulfate,a complex glycosaminoglycan with unique functional capability.Glycobiology,2018,28:182-206
67 Pomin V H.Keratan sulfate:An up-to-date review.Int J Biol Macromolecules,2015,72:282-289
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