From structural biology to designing therapy for inborn errors of metabolism

Abstract

At the SSIEM Symposium in Istanbul 2010, I presented an overview of protein structural approaches in the study of inborn errors of metabolism (Yue and Oppermann 2011). Five years on, the field is going strong with new protein structures, uncovered catalytic functions and novel chemical matters for metabolic enzymes, setting the stage for the next generation of drug discovery. This article aims to update on recent advances and lessons learnt on inborn errors of metabolism via the protein-centric approach, citing examples of work from my group, collaborators and co-workers that cover diverse pathways of transsulfuration, cobalamin and glycogen metabolism. Taking into consideration that many inborn errors of metabolism result in the loss of enzyme function, this presentation aims to outline three key principles that guide the design of small molecule therapy in this technically challenging field: (1) integrating structural, biochemical and cell-based data to evaluate the wide spectrum of mutation-driven enzyme defects in stability, catalysis and protein-protein interaction; (2) studying multi-domain proteins and multi-protein complexes as examples from nature, to learn how enzymes are activated by small molecules; (3) surveying different regions of the enzyme, away from its active site, that can be targeted for the design of allosteric activators and inhibitors.

Co‐expression with chaperones can affect protein 3D structure as exemplified by loss‐of‐function variants of human prolidase

“…LOF variants of proteins are generally little studied, and their activation poses bigger challenge that inhibition of a given activity. Nevertheless, several approaches have been investigated with some success [16]. One of the approaches was the development of so-called pharmaceutical chaperones [12], but to the best of our knowledge activation of natural protein chaperones as a way of stabilizing LOF enzymes has not been widely tested and such effect was never proved by means of structural biology.…”

“…In fact, such small molecular agents referred to as pharmaceutical chaperones [11] have been investigated for a number of targets related to protein misfolding [12,13] resulting in several drug candidates and approved drugs [14]. Yet, the development of such a stabilizing agent is usually a tedious project [11][12][13]15] and the utmost importance of structural biology was underlined in such investigations [16].…”

Tyrosine and tryptophan hydroxylases as therapeutic targets in human disease

“…Several PCs against lysosomal disorders are already in clinical trials demonstrating a promising approach toward small molecule-based therapies [119,120]. These therapeutics may be classified as active site-specific PCs, and nonactive site PCs [121]. The initially described PCs rather belonged to the first type, which were developed through derivatization of natural ligands and agonists [117,121], largely based on the realization that supplementation with cofactor and coenzymes increases the activity and stability of numerous variant enzymes [122].…”

“…These therapeutics may be classified as active site-specific PCs, and nonactive site PCs [121]. The initially described PCs rather belonged to the first type, which were developed through derivatization of natural ligands and agonists [117,121], largely based on the realization that supplementation with cofactor and coenzymes increases the activity and stability of numerous variant enzymes [122]. Indeed, a chaperone response on mutant PAH seems to be an important molecular mechanism behind BH4-responsive PKU [123].…”

“…Similarly, BH4 treatment increases TH activity and protein levels in treated mice [124]. On the other hand, it is increasingly recognized that development of non-active site PCs, especially those that show allosteric activating function, is to be preferred [121,125], since they may induce a more active, stable conformation on the target enzyme even during catalysis, without inhibiting the activity. For the AAAHs, it has been shown that several compounds effectively preserve TH activity by their weak binding to the catalytic iron through a pyrimidine nitrogen atom [126].…”