Biosynthesis of coenzyme Q in eukaryotes

Abstract

Coenzyme Q (CoQ) is a component of the electron transport chain that participates in aerobic cellular respiration to produce ATP. In addition, CoQ acts as an electron acceptor in several enzymatic reactions involving oxidation-reduction. Biosynthesis of CoQ has been investigated mainly in Escherichia coli and Saccharomyces cerevisiae, and the findings have been extended to various higher organisms, including plants and humans. Analyses in yeast have contributed greatly to current understanding of human diseases related to CoQ biosynthesis. To date, human genetic disorders related to mutations in eight COQ biosynthetic genes have been reported. In addition, the crystal structures of a number of proteins involved in CoQ synthesis have been solved, including those of IspB, UbiA, UbiD, UbiX, UbiI, Alr8543 (Coq4 homolog), Coq5, ADCK3, and COQ9. Over the last decade, knowledge of CoQ biosynthesis has accumulated, and striking advances in related human genetic disorders and the crystal structure of proteins required for CoQ synthesis have been made. This review focuses on the biosynthesis of CoQ in eukaryotes, with some comparisons to the process in prokaryotes.

Impact of Chemical Analogs of 4-Hydroxybenzoic Acid on Coenzyme Q Biosynthesis: From Inhibition to Bypass of Coenzyme Q Deficiency

“…The polyprenyl pyrophosphate (PPP, 8 ) is formed by Coq1/Pdss1-Pdss2 (Kawamukai, 2016) (Figure 1). Aromatic compounds are substrates of UbiA if their carbon C3 is activated by a carboxylic acid moiety on C1 and a group on C4 that is electron- and hydrogen bond-donor, like hydroxyl or amine groups (Wessjohann and Sontag, 1996).…”

“…4-HB is first prenylated by Coq2 (UbiA in bacteria) and then, a total of seven reactions—one decarboxylation, three hydroxylation, and three methylation—produce the fully substituted benzoquinone ring of CoQ (Figure 1). Even though the structure of CoQ was established almost 60 years ago (Lester et al, 1958; Morton, 1958), the identity of the enzymes that catalyze the decarboxylation reaction and one of the three hydroxylation reaction is still elusive in eukaryotes (Kawamukai, 2016). In addition, the pathway that converts tyrosine (3) into 4-HB is poorly characterized and the last reaction, the oxidation of 4-hydroxybenzaldehyde (4-Hbz, 4 ) to 4-HB was only recently elucidated in S. cerevisiae (Payet et al, 2016; Stefely et al, 2016).…”

β‐ RA reduces DMQ /CoQ ratio and rescues the encephalopathic phenotype in Coq9 R239X mice

“…The biosynthesis of CoQ 10 occurs in a complex biosynthetic pathway in which the 4‐hydroxybenzoic acid (4‐HB) is the initial substrate. This precursor of the benzoquinone ring of CoQ is first prenylated, and then, a total of seven reactions (one decarboxylation, three hydroxylation, and three methylation) produce the fully substituted benzoquinone ring of CoQ (Fig EV1; Kawamukai, ). One of the hydroxylation steps is catalyzed by COQ7, a hydroxylase that needs another protein, COQ9, for its stability and normal function (Garcia‐Corzo et al , ; Lohman et al , ).…”

CoQ10 Deficiency May Indicate Mitochondrial Dysfunction in Cr(VI) Toxicity

“…Evidence suggests that mutations in the genes involved in the biosynthesis of CoQ10 could cause primary and secondary CoQ10 deficiencies. They have also been linked to various clinical mitochondrial diseases [22,23]. CoQ10 deficiency could disturb mitochondrial bioenergetics and oxidative stress, as demonstrated by decreased ATP generation, increased ROS production, and cell death [24,25].…”