Reactome | Ubiquinol biosynthesis

Ubiquinol biosynthesis

Stable Identifier

R-HSA-2142789

DOI

10.3180/R-HSA-2142789.5

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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The length of the polyisoprenoid chain of ubiquinone, aka coenzyme Q (CoQ), varies depending on the species involved: it is 6 in budding yeast, Saccharomyces cerevisiae, (CoQ6) and 10 in humans (CoQ10). Most ubiquinone is naturally reduced to ubiquinol (CoQ10H2 in humans), and this form dominates in human tissues. It functions as a ubiquitous coenzyme in redox reactions, and has a central role in the electron transport chain of the inner mitochondrial membrane.to shuttle electrons from complexes I and II to complex III. It also acts as a cofactor for biosynthetic and catabolic reactions, detoxifies damaging lipid species, and engages in cellular signaling and oxygen sensing. In eukaryotes, ubiquinones/ubiquinols are also found in other membranes such as the endoplasmic reticulum, Golgi vesicles, lysosomes, peroxisomes and the plasma membrane (reviewed in Guerra & Pagliarini, 2023).

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 (Banh et al., 2021). 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 (Pelosi et al., 2024; Nicoll et al., 2024), 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 (He et al., 2014). There is some evidence of such a complex, called complex Q, in humans (Floyd et al., 2016). 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 (Nicoll et al., 2024). COQ8A and COQ8B proteins may contribute to the formation and functionality of this complex, as they can bind to most core enzymes (Floyd et al., 2016), and as COQ8B increased the in vitro activity of COQ6 via phosphorylation of COQ3 (Nicoll et al., 2024)..

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 (Kalén et al., 1990; Staiano et al., 2023).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).

Literature References

PubMed ID	Title	Journal	Year
17482885	Endogenous synthesis of coenzyme Q in eukaryotes Tran, UC, Clarke, CF	Mitochondrion	2007
37508007	Biosynthesis, Deficiency, and Supplementation of Coenzyme Q Brea-Calvo, G, Staiano, C, Mantle, D, Millichap, LE, Hargreaves, I, García-Corzo, L, Turton, N	Antioxidants (Basel)	2023
36702698	Coenzyme Q biochemistry and biosynthesis Pagliarini, DJ, Guerra, RM	Trends Biochem Sci	2023
32707086	Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia Bakhtiari, S, Brandl, U, Meitinger, T, Sturm, M, Kobeleva, X, Ghasemi Firouzabadi, S, Husain, RA, Krageloh-Mann, I, Mane, S, Riess, O, Hübner, CA, Bolduc, F, Deschauer, M, Feichtinger, RG, Döbler-Neumann, M, Hennings, JC, Klopstock, T, Beck-Woedl, S, Grimmel, M, Rostásy, K, Strom, TM, Laugwitz, L, Bevot, A, Darvish, H, Mayr, JA, Nägele, T, Huebner, AK, Ng, AC, Besse, A, Kruer, MC, Saadi, A, Marx, C, Bonnen, PE, Klockgether, T, Colleaux, L, Hartmann, H, Chiang, D, Radelfahr, F, Wortmann, SB, Haack, TB, Buchert, R, Tafakhori, A, Cordts, I, Wagner, M, Müller, AJ, Wang, ZQ	Am J Hum Genet	2020
27499296	Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function Stefely, JA, Taylor, RW, Dolan, BK, Westphall, MS, Wilkerson, EM, Veling, MT, Wrobel, RL, Kim, JP, Jochem, A, Cho, H, Coon, JJ, Xia, C, Ulbrich, A, Gromek, KA, Rensvold, JW, Bohl, SL, Beebe, ET, Pagliarini, DJ, Werner, KM, Alston, CL, Floyd, BJ, Prokisch, H, Kremer, LS, Minogue, CE	Mol Cell	2016
38425362	In vitro construction of the COQ metabolon unveils the molecular determinants of coenzyme Q biosynthesis Gottinger, A, Mascotti, ML, Alvigini, L, Mattevi, A, Nicoll, CR, Cecchini, D, Corana, F, Mannucci, B	Nat Catal	2024
11051212	Ubiquinone. Biosynthesis of quinone ring and its isoprenoid side chain. Intracellular localization Szkopinska, A	Acta Biochim Pol	2000
34471290	The polar oxy-metabolome reveals the 4-hydroxymandelate CoQ10 synthesis pathway Shi, G, Yamamoto, K, Banh, RS, Pacold, ME, Sohn, ASW, Spillier, Q, Biancur, DE, Kimmelman, AC, Jones, DR, Kim, ES	Nature	2021
38014142	COQ4 is required for the oxidative decarboxylation of the C1 carbon of Coenzyme Q in eukaryotic cells Morbiato, L, Pelosi, L, Salviati, L, Trevisson, E, Roger-Margueritat, M, Desbats, MA, Guerra, RM, Pierrel, F, Ferizhendi, KK, Agosto, C, Sánchez-Cuesta, A, García-Corzo, L, Vázquez-Fonseca, L, Alcázar-Fabra, M, Marchi, M, Wendisch, VF, Brea-Calvo, G, Pagliarini, DJ, Zanotti, G, Bartlett, AK, Tonello, F, Rascalou, B, Navas, P, Burgardt, A	bioRxiv	2023
19531029	Biosynthesis and bioproduction of coenzyme Q10 by yeasts and other organisms Kawamukai, M	Biotechnol. Appl. Biochem.	2009
28552678	Detection of 6-demethoxyubiquinone in CoQ₁₀ deficiency disorders: Insights into enzyme interactions and identification of potential therapeutics Distelmaier, F, Wedell, A, Herebian, D, Freyer, C, Mayatepek, E, Seibt, A, Bünning, G, López, LC, Prokisch, H, Wredenberg, A, Smits, SHJ, Karall, D	Mol Genet Metab	2017
24406904	Coenzyme Q supplementation or over-expression of the yeast Coq8 putative kinase stabilizes multi-subunit Coq polypeptide complexes in yeast coq null mutants Allan, CM, He, CH, Clarke, CF, Tran, UC, Xie, LX	Biochim Biophys Acta	2014
2295606	Nonaprenyl-4-hydroxybenzoate transferase, an enzyme involved in ubiquinone biosynthesis, in the endoplasmic reticulum-Golgi system of rat liver Dallner, G, Kalén, A, Chojnacki, T, Appelkvist, EL	J Biol Chem	1990
37507930	New Insights on the Uptake and Trafficking of Coenzyme Q Guile, MD, Jain, A, Clarke, CF, Anderson, KA	Antioxidants (Basel)	2023
28790927	The Role of Sulfide Oxidation Impairment in the Pathogenesis of Primary CoQ Deficiency Luna-Sánchez, M, Quinzii, CM, Kleiner, G, López, LC, Hidalgo-Gutierrez, A, Ziosi, M	Front Physiol	2017
27155576	Disruption of the human COQ5-containing protein complex is associated with diminished coenzyme Q10 levels under two different conditions of mitochondrial energy deficiency Feng, YH, Yen, HC, Wei, YH, Lee, SH, Kan, CC, Chen, CW, Liu, YC, Huang, CC, Wei, HJ	Biochim Biophys Acta	2016
26183239	Biosynthesis of coenzyme Q in eukaryotes Kawamukai, M	Biosci Biotechnol Biochem	2016