Coenzyme Q Synthesis
Mevalonate Pathway

Author: Gianpiero Pescarmona
Date: 24/03/2010


Coenzyme Q synthesis requires:

  • Tyrosine + Vit B6, Ascorbic Acid, Pantothenic Acid
  • Farnesyl diphosphate (via Polyprenyldiphosphate)
  • S-adenosyl methionine

Kegg Pathway

CoQ10 = 10 isoprenoid units

1 isoprenoid units ( 2 NADPH + 3 ATP each )

  • 2 AcetylCoA + 2 NADPH --> mevalonate
  • mevalonate + 3 ATP --> isopentenyl pirophosphate + 3 ADP + 1 CO2

1 4-hydroxybenzoate

  • K00500 phenylalanine-4-hydroxylase [EC:] 1 NADPH + 1 O2
  • K03181 chorismate--pyruvate lyase [EC:4.1.3.-] [RN:R01302]

  1. K06125 4-hydroxybenzoate hexaprenyltransferase [EC:2.5.1.-]
    [RN:R05000] Coq2
  2. K00591 hexaprenyldihydroxybenzoate methyltransferase [EC:]
    [RN:R08771] Coq3 1 SAME
  3. K06126 ubiquinone biosynthesis monooxygenase Coq6 [EC:1.14.13.-]
    [RN:R08773] 1 NADPH + 1 O2
  4. K06127 ubiquinone biosynthesis methyltransferase [EC:2.1.1.-]
    [RN:R08774] 1 SAME
  5. K06134 ubiquinone biosynthesis monooxygenase Coq7 [EC:1.14.13.-]
    [RN:R08775] 1 NADPH + 1 O2
  6. K00591 hexaprenyldihydroxybenzoate methyltransferase [EC:]
    [RN:R08781] 1 SAME

Total Balance for 1 CoQ10 molecules:

  • 24 NADPH
  • 30 ATP
  • 3 SAME

Cell localization

Endogenous Synthesis of Coenzyme Q in Eukaryotes 2007

Coq1 through Coq9 polypeptides localize to the mitochondria. In vitro mitochondria import were investigated for seven of the yeast Coq polypeptides and demonstrated to be dependent on a mitochondrial membrane potential (Yeast COQ4 encodes a mitochondrial protein required for coenzyme Q synthesis. 2001: The putative mitochondrial-targeting sequence present at the amino-terminus of the polypeptide efficiently imported it to mitochondria in a membrane-potential-dependent manner). The function and submitochondrial localization of the nine Coq proteins, required for Q biosynthesis in eukaryotes is summarized in Table 1. A model incorporating genetic and physical evidence for a yeast Q biosynthetic multi-subunit complex is shown.

Local synthesis of nuclear-encoded mitochondrial proteins in the presynaptic nerve terminal. 2001
J Neurosci Res. 2001 Jun 1;64(5):447-53.
Gioio AE, Eyman M, Zhang H, Lavina ZS, Giuditta A, Kaplan BB.

One of the central tenets in neuroscience has been that the protein constituents of distal compartments of the neuron (e.g., the axon and nerve terminal) are synthesized in the nerve cell body and are subsequently transported to their ultimate sites of function. In contrast to this postulate, we have established previously that a heterogeneous population of mRNAs and biologically active polyribosomes exist in the giant axon and presynaptic nerve terminals of the photoreceptor neurons in squid. We report that these mRNA populations contain mRNAs for nuclear-encoded mitochondrial proteins to include: cytochrome oxidase subunit 17, propionyl-CoA carboxylase (EC, dihydrolipoamide dehydrogenase (EC, and coenzyme Q subunit 7. The mRNA for heat shock protein 70, a chaperone protein known to be involved in the import of proteins into mitochondria, has also been identified. Electrophoretic gel analysis of newly synthesized proteins in the synaptosomal fraction isolated from the squid optic lobe revealed that the large presynaptic terminals of the photoreceptor neuron contain a cytoplasmic protein synthetic system. Importantly, a significant amount of the cycloheximide resistant proteins locally synthesized in the terminal becomes associated with mitochondria. PCR analysis of RNA from synaptosomal polysomes establishes that COX17 and CoQ7 mRNAs are being actively translated. Taken together, these findings indicate that proteins required for the maintenance of mitochondrial function are synthesized locally in the presynaptic nerve terminal, and call attention to the intimacy of the relationship between the terminal and its energy generating system. J. Neurosci. Res. 64:447-453, 2001.

Axonal protein synthesis and the regulation of local mitochondrial function. 2009 Fulltext

Blood mononuclear cell coenzyme Q10 concentration and mitochondrial respiratory chain succinate cytochrome-c reductase activity in phenylketonuric patients. 2002 J Inherit Metab Dis. 2002 Dec;25(8):673-9.

  • Coenzyme Q10 (CoQ10) serves as an electron carrier within the mitochondrial respiratory chain (MRC), where it is integrally involved in oxidative phosphorylation and consequently ATP production. It has recently been suggested that phenylketonuria (PKU) patients may be susceptible to a CoQ10 deficiency as a consequence of their phenylalanine-restricted diet, which avoids foods rich in CoQ10 and its precursors. Furthermore, the high phenylalanine level in PKU patients not on dietary restriction may also result in impaired endogenous CoQ10 production, as previous studies have suggested an inhibitory effect of phenylalanine on HMG-CoA reductase, the rate-controlling enzyme in CoQ10 biosynthesis. We investigated the effect of both dietary restriction and elevated plasma phenylalanine concentration on blood mononuclear cell CoQ10 concentration and the activity of MRC complex II + III (succinate:cytochrome-c reductase; an enzyme that relies on endogenous CoQ10) in a PKU patient population. The concentrations of CoQ10 and MRC complex II + III activity were not found to be significantly different between the PKU patients on dietary restriction, PKU patients off dietary restriction and the control group, although plasma phenylalanine levels were markedly different. The results from this investigation suggest that dietary restriction and the elevated plasma phenylalanine levels of PKU patients do not effect mononuclear cell CoQ10 concentration and consequently the activity of complex II + III of the MRC.


Polyisoprenoid epoxides stimulate the biosynthesis of coenzyme Q and inhibit cholesterol synthesis. 2008


Amitriptyline induces coenzyme Q deficiency and oxidative damage in mouse lung and liver., 2011

Potentiation of the toxicity of adriamycin by propranolol. 1978

Both propranolol and adriamycin are biochemically known to inhibit mitochondrial CoQ10-enzymes of myocardial tissue in vitro. Both propranolol and adriamycin are clinically known to cause cardiotoxicity. At two dose levels of propranolol which caused no deaths to mice when administered alone, significant potentiation (p less than 0.01) of the lethality of adriamycin to mice was observed. These data, projected to the clinical situation, seem to contraindicate the administration of the beta-blocker, propranolol, for the hypertension of a cancer patient who is being treated with adriamycin.

2013-02-16T18:05:06 - Riccardo Falcetto

NonMithocondrial Coenzyme Q10 Synthesis


Although the genes encoding for the CoQ10 ( Coenzyme Q10 )biosynthetic enzymes have been identified in bacteria and yeast, there is still only limited information about these synthetic enzymes in vertebrates.
The rate-limiting enzyme for the biosynthesis of CoQ10 is the enzyme that catalyzes the condensation of the polyisoprenoid chain with the benzoquinone ring.
So far, the mitochondrial COQ2 enzyme has been considered the only prenyltransferase able to catalyze this reaction.

From the laboratories of the Department of Molecular Biotechnology and Health Sciences( Molecular Biotechnology Center, University of Torino) It has been identfied UBIAD1 (a vertebrate CoQ10 prenyltransferase),as an enzyme for CoQ10 synthesis at the level of Golgi membranes, critical for oxidative stress protection (in particular, UBIAD1 protects cardiovascular tissues from eNOS-dependent oxidative stress.
It had been found out a functional link between UBIAD1, CoQ10, and NO signaling during cardiovascular development and homeostasis. ( Cell - Ubiad1 Is an Antioxidant Enzyme that Regulates eNOS Activity by CoQ10 Synthesis )

UBIAD1 ( UBIAD1 ) contains an UbiA prenyltransferase domain also present in vertebrate COQ2.
Although COQ2 encodes a mitochondrial prenyltransferase, this new enzyme UBIAD1 resides in the Golgi compartment where it produces CoQ10. While the presence of CoQ10 in nonmitochondrial membranes was previously explained by the existence of specific mechanisms for its redistribution within the cell, now formally studies demonstrate that CoQ10 are synthetized in the Golgi compartment.
In favor of these hypothesis of a Golgi-synthetized CoQ10, it has been reported that COQ6, COQ7, and COQ9, which are critical enzymes for CoQ10 maturation, are also localized in the Golgi compartment. ( PubMed )



A short protein description with the molecular function


Your Favorite Gene SigmaCOQ2UBIAD1

Protein Aminoacids Percentage
The Protein Aminoacids Percentage gives useful information on the local environment and the metabolic status of the cell (starvation, lack of essential AA, hypoxia)

Protein Aminoacids Percentage (Width 700 px)


cellular localization,
biological function

  • Enzymes
BRENDA - The Comprehensive Enzyme Information System"COQ2":"UBIAD1":
KEGG PathwaysCOQ2"UBIAD1":
Human Metabolome DatabaseCOQ2"UBIAD1":

Authors suggested that the Golgi-localized pool of CoQ10 may function in specific cells as an essential antioxidant for plasma membrane lipids that are normally derived from the Golgi compartment.
The two distinct ubiquinone prenyltransferases act to resolve different molecular functions inside the cells and in living organisms. Italian scientists found that COQ2-mediated CoQ10 production is mainly for mitochondrial respiratory chain function and energy production, whereas UBIAD1-mediated CoQ10 production is important for membrane redox signaling and protection from lipid peroxidation.

Since UBIAD1 is localized in the Golgi compartment, this enzyme might be a nonmitochondrial CoQ10 prenyltransferase. To test this, laboratories performed subcellular fractionation experiments on human ECs and detected UBIAD1 only in Golgi compartments and not in mitochondria.
Studies about de novo CoQ10 synthesis in these subcellular fractions by incubating ECs with the hydroxy-4-benzoic acid- 13 C 6 precursor and observed a decrease in CoQ10- 13 C 6
production in Golgi compartments compared to mitochondrial fractions when UBIAD1 expression is reduced.
These data indicate that UBIAD1 is a CoQ10 biosynthetic enzyme located in the Golgi membrane compartment where large amounts of cellular CoQ10 are normally synthesized.

Ubiad1 and CoQ10: An Antioxidant System Controlling Redox Cellular Membrane in Cardiovascular Tissues

Oxidative damage is caused by an imbalance between the production of ROS and the antioxidant network.
Although ROS are predominantly implicated in causing cell damage and premature aging via oxidation of DNA, lipids, and proteins, they also play a major physiological role in several aspects of intracellular signaling and regulation, especially in cardiovascular tissues. Therefore, heart, endothelial, and vascular smooth-muscle cells need an efficient antioxidant network to balance ROS levels.

It had been shown a set of genetic and cellular data that reveal an unexpected role for UBIAD1 as an essential antioxidant gene with
important functions in the protection of heart and endothelial cells from oxidative stress at the level of cellular membranes by producing CoQ10 in the Golgi for distribution to nonmitochondrial membranes throughout the cell. In addition to its crucial role in oxidative phosphorylation, CoQ10 plays another vital role in cellular function as an antioxidant molecule.

The antioxidant nature of CoQ10 is derived from its function as an electron carrier: in this role, CoQ10 continually shuttles between oxidized and reduced forms. As it accepts electrons, it becomes reduced. As it gives up electrons, it becomes oxidized. In its reduced ubiquinol form, the CoQ10 molecule will quite easily give up one electron, and thus act as an antioxidant.
In such a way, CoQ10 inhibits lipid peroxidation by acting as a chain breaking antioxidant.
Moreover, CoQH2 reduces the initial lipid peroxyl radical, with concomitant formation of ubisemiquinone and an alkyl peroxide.
This quenching of the initiating peroxyl radicals thereby prevents the propagation of lipid peroxidation and protects not only lipids, but also proteins from oxidation.
In addition, the reduced form of CoQ10 might also contribute to the stabilization of the plasma membrane, regenerating antioxidants such as a-tocopherol.
A crucial role in all these processes is played by NADH-dependent reductase(s) acting at the plasma membrane to regenerate the reduced ubiquinol form of CoQ10, contributing to the maintainance of its antioxidant properties.
This finding also opens an interesting link among cellular redox-state and metabolic pathways such as the mevalonate pathway.
( UBIAD1......vascular endothelial cell survival and development )

An Essential Function for Ubiad1/CoQ10 in Regulation of NO Signaling

UBIAD1 protects cardiovascular tissue from ROS-mediated oxidative stress by producing CoQ10 located in Golgi and plasma membranes. Major enzymatic pathways responsible for the generation of ROS in cardiovascular tissues are mainly NADPH oxidases and eNOS.
By using drug inhibition and gene inactivation approaches, it has been identified eNOS dysfunction as the primary cause of ROS increase in bar mutant and UBIAD1-silenced human ECs.

bar or barolo gene encodes Ubiad1 (UbiA-domain containing protein 1)


The NO synthetized by eNOS is an essential factor for cardiovascular development and homeostasis in vertebrates.
It has been suggested that CoQ10 might have a positive role in modulating NO-related pathways by recoupling eNOS in endothelial cells.
eNOS is a ‘‘L-arginine, NADPH:oxygen oxidoreductases, NO-forming enzyme’’ that couples reduction of molecular oxygen to L-arginine oxidation and generation of L-citrulline and NO.

eNOS controls the flow of electrons donated by NADPH to flavins FAD and FMN in the reductase domain of one monomer through BH4 to the ferrous-dioxygen complex (Fe) in the oxygenase domain.
When NADPH and BH4 cofactors are limiting, electron transfer becomes uncoupled from L-arginine oxidation, the ferrous–dioxygen complex dissociates, and superoxide (O 2 - ) is generated from the oxygenase domain.


barolo mutants lacking the Golgi pool of CoQ10 die due to the accumulation of oxidative damage in cardiovascular tissues caused by ROS produced by eNOS.


Likely there is a mechanism whereby UBIAD1 is required in the Golgi compartment to produce CoQ10 as an important cofactor for eNOS-mediated NO production.
This model could fit with the oxido-reductive properties of CoQ10 and eNOS: the electron flux inside eNOS that is mandatory to produce NO from L-arginine might require CoQ10, together with NADPH and BH4. Such function would not be very different from what CoQ10 does in the mitochondrial electron transport chain (ETC) coupling electron transfer between an electron donor (such as NADH) and an electron acceptor (such as O 2 ) with the transfer of H + ions across the mitochondrial inner membrane.

In the Golgi membranes, the flow of electrons within eNOS transfers electrons from NADPH to the flavins FAD and FMN, which have the capacity to reduce molecular oxygen.
If the ETC is disturbed, such as in the absence of UBIAD1/CoQ10, the ferrous-dioxygen complex dissociates, and O 2- is generated from the FMN oxygenase domain.
In cardiovascular tissues, the CoQ10 produced by UBIAD1 in the Golgi compartment may be an important cofactor to maintain eNOS in a coupled conformation (e.g., required to produce physiological NO) and, eventually, quench leaking-uncoupled electrons.

When UBIAD1/CoQ10 in the Golgi compartment is absent or decreased (bar mutants and siUBIAD1-treated cells) eNOS switches to an ‘‘uncoupled’’ conformation, producing oxidative species instead of NO and causing cardiovascular oxidative damage.


Further experiments need to be done to assess this hypothesis as well as the possibility that other NOS (e.g., nNOS) could be affected by the lack of Ubiad1 in vivo.
Moreover, UBIAD1 catalyzes reactions in a pathway with important therapeutic implications for cardiovascular failure, such as the opportunity to decrease oxidative damage and counteract some of the side effects of statins. In addition, pharmacological or genetic stimulation of UBIAD1, as a CoQ10 biosynthetic enzyme, represents a promising therapeutic approach for antioxidant-related diseases such as aging and cancer.

Riccardo Falcetto & Ilaria Fumi

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