Humans have lost the ability to convert urate into the more soluble allantoin with the evolutionary inactivation of three enzymes of the uricolytic pathway. Restoration of this function through enzyme replacement therapy can treat severe hyperuricemia and Lesch-Nyhan disease. Through a genomic exploration of natural gene fusions, we found that plants and diatoms independently evolved a fusion protein (allantoin synthase) complementing two human pseudogenes. The 1.85-Å-resolution crystal structure of allantoin synthase from the diatom Phaeodactylum tricornutum provides a rationale for the domain combinations observed in the metabolic pathway, suggesting that quaternary structure is key to the evolutionary success of protein domain fusions. Polyethylene glycol (PEG) conjugation experiments indicate that a PEG-modified form of the natural fusion protein provides advantages over separate enzymes in terms of activity maintenance and manufacturing of the bioconjugate. These results suggest that the combination of different activities in a single molecular unit can simplify the production and chemical modification of recombinant proteins for multifunctional enzyme therapy.

Diatom Allantoin Synthase Provides Structural Insights into Natural Fusion Protein Therapeutics / Oh, Juntaek; Liuzzi, Anastasia; Ronda, Luca; Marchetti, Marialaura; Corsini, Romina; Folli, Claudia; Bettati, Stefano; Rhee, Sangkee; Percudani, Riccardo. - In: ACS CHEMICAL BIOLOGY. - ISSN 1554-8929. - 13:8(2018), pp. 2237-2246. [10.1021/acschembio.8b00404]

Diatom Allantoin Synthase Provides Structural Insights into Natural Fusion Protein Therapeutics

Anastasia Liuzzi;Luca Ronda;Marialaura Marchetti;Romina Corsini;Claudia Folli;Stefano Bettati;Riccardo Percudani
2018-01-01

Abstract

Humans have lost the ability to convert urate into the more soluble allantoin with the evolutionary inactivation of three enzymes of the uricolytic pathway. Restoration of this function through enzyme replacement therapy can treat severe hyperuricemia and Lesch-Nyhan disease. Through a genomic exploration of natural gene fusions, we found that plants and diatoms independently evolved a fusion protein (allantoin synthase) complementing two human pseudogenes. The 1.85-Å-resolution crystal structure of allantoin synthase from the diatom Phaeodactylum tricornutum provides a rationale for the domain combinations observed in the metabolic pathway, suggesting that quaternary structure is key to the evolutionary success of protein domain fusions. Polyethylene glycol (PEG) conjugation experiments indicate that a PEG-modified form of the natural fusion protein provides advantages over separate enzymes in terms of activity maintenance and manufacturing of the bioconjugate. These results suggest that the combination of different activities in a single molecular unit can simplify the production and chemical modification of recombinant proteins for multifunctional enzyme therapy.
2018
Diatom Allantoin Synthase Provides Structural Insights into Natural Fusion Protein Therapeutics / Oh, Juntaek; Liuzzi, Anastasia; Ronda, Luca; Marchetti, Marialaura; Corsini, Romina; Folli, Claudia; Bettati, Stefano; Rhee, Sangkee; Percudani, Riccardo. - In: ACS CHEMICAL BIOLOGY. - ISSN 1554-8929. - 13:8(2018), pp. 2237-2246. [10.1021/acschembio.8b00404]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2850911
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