Ubiquinol biosynthesis

Ubiquinol/ubiquinone is synthesized in the following way. Initially, mitochondrial 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) processes 4-hydroxphenylpyruvate (HPP, HPPA) to (S)-4-hydroxymandelate (4-HMA). HPDL defects lead to CoQ10 deficiency. The HPDL product 4-HMA is a precursor for the synthesis of 4-hydroxybenzoate (PHB), from which the CoQ10 head group is derived. Because HPDL is a mitochondrial protein, cytosolic HPP from tyrosine catabolism must either be imported by a yet unknown transport mechanism or mitochondrial HPP could be the product of an unknown mitochondrial reaction (Husain et al., 2020; reviewed in Staiano et al., 2023). A polyprenyl diphosphate synthase (PDSS1-2) assembles the polyisoprenoid tail. Next, 4-hydroxybenzoate polyprenyltransferase (COQ2) catalyzes the formation of the covalent linkage between PHB and the polyisoprenoid tail to produce 4-hydroxy-3-polyprenyl benzoic acid intermediate (DHB, 3-decaprenyl-4-hydroxybenzoic acid in humans). Modifications of the aromatic ring follow and involve an oxidative decarboxylation, two hydroxylations, two O-methylations, one C-methylation. This series of reactions, which precise order is not fully established, especially regarding the oxidative decarboxylation step, yield the fully substituted hydroquinone, ubiquinol (reviewed in Guerra & Pagliarini, 2023).

Homologs of the core enzymes COQ3, COQ4, COQ5, COQ6, COQ7, and COQ9 have been shown to form a membrane-localized multienzyme complex ("COQ synthome") in yeast. There is some evidence of such a complex, called complex Q, in humans. A complex was reconstituted in vitro with ancestral versions of COQ3-7 and COQ9, and was able to convert a short chain analog of DHB (4-Hydroxy-3-(3-methylbut-2-en-1-yl)benzoic acid) into CoQ1. COQ8A and COQ8B proteins may contribute to the formation and functionality of this complex, as they can bind to most core enzymes, and as COQ8B increased the in vitro activity of COQ6 via phosphorylation of COQ3..

Parts of CoQ10 synthesis may also occur in the Golgi and endoplasmic reticulum membranes, adding to the cellular membrane CoQ10 pool. The relevance of such processes seems minor.The precise function of two other genes, COQ10A and COQ10B, which appear to be quinone-binding proteins, is still under investigation. Most of the time, CoQ10 is transported out of the mitochondrion and to the plasma membrane by isoforms of the STARD7 lipid carrier (reviewed in Guile et al., 2023).

CoQ10 deficiency, which can result from reduced activity of any biosynthesis core enzymes or the COQ8A, and COQ8B proteins, has significant implications. It is associated with several inherited metabolic disorders, the phenotypes of which are extremely heterogeneous. These disorders range from fatal neonatal presentations with multisystem involvement to adult-onset isolated myopathy. However, in many cases, the symptoms can be ameliorated by nutritional supplementation with CoQ10 (reviewed in Quinzii et al., 2017; Staiano et al., 2023).