Structural Basis of Cooperativity in Human UDP-Glucose Dehydrogenase

Rajakannan, V.; Lee, Hui Sun; Chong, Seon Ha; Ryu, Han Bong; Bae, Ji Young; Whang, Eun Young; Huh, Jae-Wan; Cho, Sung Woo; Kang, Lin Woo; Choe, Han; Robinson, Robert

doi:10.1371/journal.pone.0025226

“…UGDH mutations behave as hypomorphic alleles. The UGDH oxidoreductase consists of three distinct domains 14 : the NADbinding (N-terminal) and UDP-binding (C-terminal) domains, and an internal domain that bridges the two termini together 14 . The UGDH enzyme assembles into a disc-shaped double layer composed of a trimer of dimers 6 (Suppl.…”

Section: Resultsmentioning

confidence: 99%

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Hengel

¹

,

Bosso-Lefèvre

²

,

Grady

³

et al. 2020

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Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.

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“…Arg244{393} (76%) from subunit b of the dimer is 3.1 Å from 2″ hydroxyl group of glucose in UDP‐glucose bound in subunit a, and vice versa . This intersubunit contact may participate in the communication that results in half‐sites reactivity in mammalian UDPGDHs . Asn325{491} in SpUDPGDH is at a position in the alignment that is 80% aspartate.…”

Section: Resultsmentioning

confidence: 99%

“…In SpUDPGDH index 406 is occupied by Gly255{406}, which is 5. 6 A from the oxygen at position 2 of the uridine ring in UDP-Glc. Thus, Ala263{406} allows for the proper shape of the binding pocket for the nucleotide of GDP-Man in GDPMDHs.…”

Section: Group Entropy Analysis Of Gdpmdhsmentioning

confidence: 99%

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Analysis of nucleotide diphosphate sugar dehydrogenases reveals family and group‐specific relationships

Freas

¹

,

Newton

²

,

Perozich

³

2016

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UDP ‐glucose dehydrogenase ( UDPGDH ), UDP ‐ N ‐acetyl‐mannosamine dehydrogenase ( UDPNAMDH ) and GDP ‐mannose dehydrogenase ( GDPMDH ) belong to a family of NAD + ‐linked 4‐electron‐transfering oxidoreductases called nucleotide diphosphate sugar dehydrogenases ( NDP ‐ SDH s). UDPGDH is an enzyme responsible for converting UDP ‐ d ‐glucose to UDP ‐ d ‐glucuronic acid, a product that has different roles depending on the organism in which it is found. UDPNAMDH and GDPMDH convert UDP ‐ N ‐acetyl‐mannosamine to UDP ‐ N ‐acetyl‐mannosaminuronic acid and GDP ‐mannose to GDP ‐mannuronic acid, respectively, by a similar mechanism to UDPGDH . Their products are used as essential building blocks for the exopolysaccharides found in organisms like Pseudomonas aeruginosa and Staphylococcus aureus . Few studies have investigated the relationships between these enzymes. This study reveals the relationships between the three enzymes by analysing 229 amino acid sequences. Eighteen invariant and several other highly conserved residues were identified, each serving critical roles in maintaining enzyme structure, coenzyme binding or catalytic function. Also, 10 conserved motifs that included most of the conserved residues were identified and their roles proposed. A phylogenetic tree demonstrated relationships between each group and verified group assignment. Finally, group entropy analysis identified novel conservations unique to each NDP ‐ SDH group, including residue positions critical to NDP ‐sugar substrate interaction, enzyme structure and intersubunit contact. These positions may serve as targets for future research. Enzymes UDP ‐glucose dehydrogenase (UDPGDH, EC 1.1.1.22 ).

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“…The enzyme uridine diphosphoglucose dehydrogenase (UDPGD) is exclusively responsible for the conversion of uridine diphosphoglucose (UDP) to UDP-glucuronic acid [122]. In turn, UDP-glucuronic acid is essential for the synthesis of a number of GAGs, including hyaluronan, chondroitin sulfate, and heparin sulfate [123].…”

Section: Shared Properties Of Sdscs and Ncsmentioning

confidence: 99%

Reconstruction of an In Vitro Niche for the Transition from Intervertebral Disc Development to Nucleus Pulposus Regeneration

Shoukry

¹

,

Li

²

,

Pei

³

2013

Stem Cells and Development

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The nucleus pulposus (NP) plays a prominent role in both the onset and progression of intervertebral disc degeneration. While autologous repair strategies have demonstrated some success, their in vitro culture system is outdated and insufficient for maintaining optimally functioning cells through the required extensive passaging. Consequently, the final population of cells may be unsuitable for the overwhelming task of repairing tissue in vivo and could result in subpar clinical outcomes. Recent work has identified synovium-derived stem cells (SDSCs) as a potentially important new candidate. This population of precursors can promote matrix regeneration and additionally restore the balance of catabolic and anabolic metabolism of surrounding cells. Another promising application is their ability to produce an extracellular matrix in vitro that can be modified via decellularization to produce a tissue-specific substrate for efficient cell expansion, while retaining chondrogenic potential. When combined with hypoxia, soluble factors, and other environmental regulators, the resultant complex microenvironment will more closely resemble the in vivo niche, which further improves the cell capacity, even after extensive passaging. In this review, the adaptive mechanisms NP cells utilize in vivo are considered for insight into what factors are important for constructing a tissue-specific in vitro niche. Evidence for the use of SDSCs for NP regeneration is also discussed. Many aspects of NP behavior are still unknown, which could lead to future work yielding key information on producing sufficient numbers of a high-quality NPspecific population that is able to regenerate deteriorated NP in vivo.

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Structural Basis of Cooperativity in Human UDP-Glucose Dehydrogenase

Cited by 12 publications

References 46 publications

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Analysis of nucleotide diphosphate sugar dehydrogenases reveals family and group‐specific relationships

Reconstruction of an In Vitro Niche for the Transition from Intervertebral Disc Development to Nucleus Pulposus Regeneration

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