Thiophosphate Analogs of Coenzyme A and Its Precursors-Synthesis, Stability, and Biomimetic Potential

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2022 Aug 26

PMID 36008959

Authors

Christian Locherer

Elif Tosun

Hannah Backes

Andres Jaschke

Affiliations

Soon will be listed here.

Abstract

Coenzyme A (CoA) is ubiquitous and essential for key cellular processes in any living organism. Primary degradation of CoA occurs by enzyme-mediated pyrophosphate hydrolysis intracellularly and extracellularly to form adenosine 3',5'-diphosphate and 4'-phosphopantetheine (PPanSH). The latter can be recycled for intracellular synthesis of CoA. Impairments in the CoA biosynthetic pathway are linked to a severe form of neurodegeneration with brain iron accumulation for which no disease-modifying therapy is available. Currently, exogenous administration of PPanSH is examined as a therapeutic intervention. Here, we describe biosynthetic access to thiophosphate analogs of PPanSH, 3'-dephospho-CoA, and CoA. The stabilizing effect of thiophosphate modifications toward degradation by extracellular and peroxisomal enzymes was studied in vitro. Experiments in a CoA-deficient cell model suggest a biomimetic potential of the PPanSH thiophosphate analog PPanSH (C1). According to our findings, the administration of PPanSH may provide an alternative approach to support intracellular CoA-dependent pathways.

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