Innovative therapy for Classic Galactosemia — Tale of two HTS

Tang, Manshu; Odejinmi, S.I.; Vankayalapati, Hariprasad; Wierenga, Klaas J.; Lai, Kent

doi:10.1016/j.ymgme.2011.09.028

Cited by 49 publications

(41 citation statements)

References 124 publications

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“…Focus has been on substrate reduction therapies by targeting GALK1 to decrease galactose-1-phosphate concentrations (48), and recently superoxide dismutase mimics appear to treat a fruit fly model of galactosemia (49). Another therapeutic approach would be to increase the activity of hGALT, either by enzyme replacement therapy or by small-molecule chemical/pharmacological chaperones (31,40,50,51).…”

Section: Discussionmentioning

confidence: 99%

Molecular basis of classic galactosemia from the structure of human galactose 1-phosphate uridylyltransferase

et al. 2016

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Classic galactosemia is a potentially lethal disease caused by the dysfunction of galactose 1-phosphate uridylyltransferase (GALT). Over 300 disease-associated GALT mutations have been reported, with the majority being missense changes, although a better understanding of their underlying molecular effects has been hindered by the lack of structural information for the human enzyme. Here, we present the 1.9 Å resolution crystal structure of human GALT (hGALT) ternary complex, revealing a homodimer arrangement that contains a covalent uridylylated intermediate and glucose-1-phosphate in the active site, as well as a structural zinc-binding site, per monomer. hGALT reveals significant structural differences from bacterial GALT homologues in metal ligation and dimer interactions, and therefore is a zbetter model for understanding the molecular consequences of disease mutations. Both uridylylation and zinc binding influence the stability and aggregation tendency of hGALT. This has implications for disease-associated variants where p.Gln188Arg, the most commonly detected, increases the rate of aggregation in the absence of zinc likely due to its reduced ability to form the uridylylated intermediate. As such our structure serves as a template in the future design of pharmacological chaperone therapies and opens new concepts about the roles of metal binding and activity in protein misfolding by disease-associated mutants.

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Section: Discussionmentioning

confidence: 99%

Molecular basis of classic galactosemia from the structure of human galactose 1-phosphate uridylyltransferase

et al. 2016

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“…Despite no improvements in cognitive function, it remains to be clarified whether uridine was able to enter the cells (Tang et al 2012). …”

Section: Therapeutic Approaches In Classic Galactosemiamentioning

confidence: 99%

Sweet and sour: an update on classic galactosemia

Coelho

Rubio-Gozalbo

Vicente

et al. 2017

J of Inher Metab Disea

109

125

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Classic galactosemia is a rare inherited disorder of galactose metabolism caused by deficient activity of galactose-1-phosphate uridylyltransferase (GALT), the second enzyme of the Leloir pathway. It presents in the newborn period as a life-threatening disease, whose clinical picture can be resolved by a galactose-restricted diet. The dietary treatment proves, however, insufficient in preventing severe long-term complications, such as cognitive, social and reproductive impairments. Classic galactosemia represents a heavy burden on patients’ and their families’ lives. After its first description in 1908 and despite intense research in the past century, the exact pathogenic mechanisms underlying galactosemia are still not fully understood. Recently, new important insights on molecular and cellular aspects of galactosemia have been gained, and should open new avenues for the development of novel therapeutic strategies. Moreover, an international galactosemia network has been established, which shall act as a platform for expertise and research in galactosemia. Herein are reviewed some of the latest developments in clinical practice and research findings on classic galactosemia, an enigmatic disorder with many unanswered questions warranting dedicated research.

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“…[1][2][3] This enzyme catalyzes the conversion of galactose-1-phosphate and uridinediphosphate glucose (UDP-glucose) to uridine-diphosphate galactose (UDP-galactose) and glucose-1-phosphate. [1][2][3][4][5] Longterm outcomes in classic galactosemia include impaired cognition, speech apraxia, ataxia, 3-7 infertility, and reduced bone mineral density. 8 Two common mutations, Q188R and K285N, account for more than 70% of GALT alleles in Caucasians and are associated with classic galactosemia and impaired GALT function.…”

Section: Discussionmentioning

confidence: 99%

Neurologic Sequela in a Patient With Galactosemia Potentially Mediated by Interleukin-11 Dysfunction

Winter

Ben‐Pazi

2014

J Child Neurol

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A 16-year-old galactosemic patient, homozygous for the 5.5-kb gene deletion, suffered severe neurologic regression following streptococcal infection. Since the gene deletion includes the promoter of interleukin-11a receptor involved in neuronal apoptosis, we questioned whether this patient had no interleukin-11a receptor activity-resulting in neuronal toxicity during septicemia. We hypothesized that interleukin-11 levels would be elevated because of a loss of feedback induced by the absent interleukin-11Ra receptor complex. To assess this, we compared interleukin-11 levels in the proband and 2 of his siblings with the same genetic deletion, to age-matched controls. No differences were found in interleukin-11 levels between groups. Our study was not carried out during acute infective states, when the disrupted immunoregulation triggered by sepsis is relevant, and is thus limited. In conclusion, although interleukin-11 was not chronically elevated in individuals with galactosemia and 5.5-kb gene deletion, data do not rule out potential interleukin-11 dysfunction during acute infection.

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Innovative therapy for Classic Galactosemia — Tale of two HTS

Cited by 49 publications

References 124 publications

Molecular basis of classic galactosemia from the structure of human galactose 1-phosphate uridylyltransferase

Molecular basis of classic galactosemia from the structure of human galactose 1-phosphate uridylyltransferase

Sweet and sour: an update on classic galactosemia

Neurologic Sequela in a Patient With Galactosemia Potentially Mediated by Interleukin-11 Dysfunction

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