A Trivalent Enzymatic System for Uricolytic Therapy of HPRT Deficiency and Lesch-Nyhan DiseaseReportar como inadecuado

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Pharmaceutical Research

, Volume 34, Issue 7, pp 1477–1490

First Online: 15 May 2017Received: 28 February 2017Accepted: 25 April 2017


PurposeBecause of the evolutionary loss of the uricolytic pathway, humans accumulate poorly soluble urate as the final product of purine catabolism. Restoration of uricolysis through enzyme therapy is a promising treatment for severe hyperuricemia caused by deficiency of hypoxanthine-guanine phosphoribosyltransferase HPRT. To this end, we studied the effect of PEG conjugation on the activity and stability of the enzymatic complement required for conversion of urate into the more soluble S-allantoin.

MethodsWe produced in recombinant form three zebrafish enzymes required in the uricolytic pathway. We carried out a systematic study of the effect of PEGylation on the function and stability of the three enzymes by varying PEG length, chemistry and degree of conjugation. We assayed in vitro the uricolytic activity of the PEGylated enzymatic triad.

ResultsWe defined conditions that allow PEGylated enzymes to retain native-like enzymatic activity even after lyophilization or prolonged storage. A combination of the three enzymes in an appropriate ratio allowed efficient conversion of urate to S-allantoin with no accumulation of intermediate metabolites.

ConclusionsPharmaceutical restoration of the uricolytic pathway is a viable approach for the treatment of severe hyperuricemia.

KEY WORDSenzyme therapy gout hyperuricemia Lesch-Nyhan disease polyethylene glycol purine degradation AbbreviationsASAAccessible surface area

GMPGuanosine monophosphate


HPRTHypoxanthine-guanine phosphoribosyltransferase

IMPInosine monophosphate


LNDLesch-Nyhan disease



PEGPolyethylene glycol

PRPPPhosphoribosyl pyrophosphate


UoxUrate oxidase

UradOHCU decarboxylase

UrahHIU hydrolase

Electronic supplementary materialThe online version of this article doi:10.1007-s11095-017-2167-6 contains supplementary material, which is available to authorized users.

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Autor: Luca Ronda - Marialaura Marchetti - Riccardo Piano - Anastasia Liuzzi - Romina Corsini - Riccardo Percudani - Stefano Betta

Fuente: https://link.springer.com/

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