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A Trivalent Enzymatic System for Uricolytic Therapy of HPRT Deficiency and Lesch-Nyhan Disease
A Trivalent Enzymatic System for Uricolytic Therapy of HPRT Deficiency and Lesch-Nyhan Disease
- Source :
- Pharmaceutical Research
- Publication Year :
- 2017
- Publisher :
- Springer US, 2017.
-
Abstract
- Purpose Because 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. Methods We 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. Results We 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. Conclusions Pharmaceutical restoration of the uricolytic pathway is a viable approach for the treatment of severe hyperuricemia. Electronic supplementary material The online version of this article (doi:10.1007/s11095-017-2167-6) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Hypoxanthine Phosphoribosyltransferase
Lesch-Nyhan Syndrome
Urate Oxidase
Carboxy-Lyases
Pharmaceutical Science
01 natural sciences
Polyethylene Glycols
chemistry.chemical_compound
Pharmacology (medical)
Hyperuricemia
Allantoin
Zebrafish
chemistry.chemical_classification
biology
Urate oxidase
Stereoisomerism
Uricosuric Agents
Recombinant Proteins
Biochemistry
Hypoxanthine-guanine phosphoribosyltransferase
polyethylene glycol
Molecular Medicine
Phosphoribosyltransferase
Biotechnology
Research Paper
purine degradation
Enzyme Therapy
010402 general chemistry
Amidohydrolases
03 medical and health sciences
gout
medicine
Animals
Humans
Pharmacology
Organic Chemistry
Lesch-Nyhan disease
medicine.disease
0104 chemical sciences
Uric Acid
Molecular Weight
030104 developmental biology
Enzyme
chemistry
Solubility
biology.protein
Uric acid
Lesch–Nyhan syndrome
Subjects
Details
- Language :
- English
- ISSN :
- 1573904X and 07248741
- Volume :
- 34
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Pharmaceutical Research
- Accession number :
- edsair.doi.dedup.....3d7aba51dbfd2f16705c8c207102d0bf