Investigation of the biological functions of heparan sulfate using a chemoenzymatic synthetic approach

Wang, Zhangjie; Arnold, Katelyn; Dhurandhare, Vijay M.; Xu, Yongmei; Liu, Jian

doi:10.1039/d0cb00199f

Cited by 19 publications

(13 citation statements)

References 68 publications

(74 reference statements)

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“…This method makes use of recombinant glycosyltransferases and sulfotransferases to efficiently produce the desired product, in contrast to tediously purifying heterogeneous compounds from source (Xu et al, 2017a;Xu et al, 2011;Zhang et al, 2020). Currently this process is being utilized for the development of improved anticoagulant and autoinflammatory therapeutics to treat acute liver failure due to acetaminophen overdose (Arnold et al, 2020;Wang et al, 2021;Xu et al, 2014;Xu et al, 2017a).…”

Section: Future Directions: Utilizing Sulfotransferase Structures For...mentioning

confidence: 99%

From Steroid and Drug Metabolism to Glycobiology, Using Sulfotransferase Structures to Understand and Tailor Function

Pedersen

et al. 2022

Drug Metab Dispos

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Sulfotransferases are ubiquitous enzymes that transfer a sulfo group (SO 3 ) from the universal cofactor donor PAPS to a broad range of acceptor substrates. In humans, the cytosolic sulfotransferases (SULTs) are involved in the sulfation of endogenous compounds such as steroids, neurotransmitters, hormones and bile acids as well as xenobiotics including drugs, toxins and environmental chemicals. The Golgi associated membrane-bound sulfotransferases are involved in post-translational modification of macromolecules from glycosaminoglycans to proteins. The sulfation of small molecules can have profound biological effects on the functionality of the acceptor, including activation, deactivation or enhanced metabolism and elimination. Sulfation of macromolecules has been shown to regulate a number of physiological and pathophysiological pathways by enhancing binding affinity to regulatory proteins or binding partners. Over the last 25 years, crystal structures of these enzymes have provided a wealth of information on the mechanisms of this process and the specificity of these enzymes. This review will focus on the general commonalities of the sulfotransferases, from enzyme structure to catalytic mechanism as well as providing examples into how structural information is being utilized to either design drugs that inhibit sulfotransferases or to modify the enzymes to improve drug synthesis.

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Section: Future Directions: Utilizing Sulfotransferase Structures For...mentioning

confidence: 99%

From Steroid and Drug Metabolism to Glycobiology, Using Sulfotransferase Structures to Understand and Tailor Function

Pedersen

et al. 2022

Drug Metab Dispos

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“…In this review we focus on chemical approaches to and methodology improvements for the synthesis of H/HS from 2015 onwards. Contextually, this should be considered alongside the impressive and complimentary advances in chemoenzymatic approaches to access H/HS that have been well reviewed elsewhere, [9,10] alongside GAG synthesis approaches in general. [11] We first consider advances towards the synthesis of the heparin pentasaccharide fondaparinux (and analogues), followed by HS targets, including building block synthesis, oligosaccharide construction and chemical sulfation methods.…”

Section: Introductionmentioning

confidence: 99%

Developments in the Chemical Synthesis of Heparin and Heparan Sulfate

Pongener

O'Shea

Wootton

et al. 2021

The Chemical Record

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Heparin and heparan sulfate represent key members of the glycosaminoglycan family of carbohydrates and underpin considerable repertoires of biological importance. As such, their efficiency of synthesis represents a key requirement, to further understand and exploit the H/HS structure‐to‐biological function axis. In this review we focus on chemical approaches to and methodology improvements for the synthesis of these essential sugars (from 2015 onwards). We first consider advances in accessing the heparin‐derived pentasaccharide anticoagulant fondaparinux. This is followed by heparan sulfate targets, including key building block synthesis, oligosaccharide construction and chemical sulfation techniques. We end with a consideration of technological improvements to traditional, solution‐phase synthesis approaches that are increasingly being utilised.

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“…6,7 The availability of structurally defined oligosaccharides accelerates efforts to study the relationship between the structure and function of HS and the development of HSbased therapeutics. 8,9 One example is the synthesis of anticoagulant dodecasaccharides to replace animal-sourced low-molecular-weight heparin. 7,9 Synthetic heparin reduces side effects and improves the safety of the supply chain for heparin and low-molecular-weight heparin drugs.…”

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confidence: 99%

“…High regioselectivity displayed by HS biosynthetic enzymes has eliminated the need for protection and deprotection steps used in chemical synthesis. As a result, enzyme-based synthesis has dramatically increased the synthesis efficiency, making it a promising alternative approach to synthesize structurally homogeneous oligosaccharides. , The availability of structurally defined oligosaccharides accelerates efforts to study the relationship between the structure and function of HS and the development of HS-based therapeutics. , One example is the synthesis of anticoagulant dodecasaccharides to replace animal-sourced low-molecular-weight heparin. , Synthetic heparin reduces side effects and improves the safety of the supply chain for heparin and low-molecular-weight heparin drugs. The 3-OST isoform 5 (3-OST-5) is a key enzyme used in the process of preparing the anticoagulant dodecasaccharides. , …”

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confidence: 99%

Structural and Substrate Specificity Analysis of 3-O-Sulfotransferase Isoform 5 to Synthesize Heparan Sulfate

et al. 2021

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Heparan sulfate 3-O-sulfotransferase (3-OST) transfers a sulfo group to the 3-OH position of a glucosamine saccharide unit to form 3-O-sulfated heparan sulfate. 3-O-sulfation is known to be critically important for bestowing anticoagulant activity and other biological functions of heparan sulfate. Here, we report two ternary crystal structures of 3-OST isoform 5 (3-OST-5) with 3′-phosphoadenosine-5′-phosphate (PAP) and two octasaccharide substrates. We also used 3-OST-5 to synthesize six 3-Osulfated 8-mers. Results from the structural analysis of the six 3-O-sulfated 8-mers revealed the substrate specificity of 3-OST-5. The enzyme prefers to sulfate a 6-O-sulfo glucosamine saccharide that is surrounded by glucuronic acid over a 6-O-sulfo glucosamine saccharide that is surrounded by 2-O-sulfated iduronic acid. 3-OST-5-modified 8-mers display a broad range of anti-factor Xa activity, depending on the structure of the 8-mer. We also discovered that the substrate specificity of 3-OST-5 is not governed solely by the side chains from amino acid residues in the active site. The conformational flexibility of the 2-O-sulfated iduronic acid in the saccharide substrates also contributes to the substrate specificity. These findings advance our understanding of how to control the biosynthesis of 3-O-sulfated heparan sulfate with the desired biological activities.

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Investigation of the biological functions of heparan sulfate using a chemoenzymatic synthetic approach

Abstract: Heparan sulfate (HS) is a highly sulfated polysaccharide playing essential physiological and pathophysiological roles in the animal kingdom. Heparin, a highly sulfated form of HS, is a widely used anticoagulant...

Cited by 19 publications

References 68 publications

From Steroid and Drug Metabolism to Glycobiology, Using Sulfotransferase Structures to Understand and Tailor Function

From Steroid and Drug Metabolism to Glycobiology, Using Sulfotransferase Structures to Understand and Tailor Function

Developments in the Chemical Synthesis of Heparin and Heparan Sulfate

Structural and Substrate Specificity Analysis of 3-O-Sulfotransferase Isoform 5 to Synthesize Heparan Sulfate

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