Coenzyme Q

DATA No : VCQ0001 INFORMANT : Tetsuya Nakamura

NAME : 2,5-cyclohexadiene-1,4-dione,2-(3,7,11,15,19,23,27,31,35,39-decamethyl- 2,6,10,14,18,22,26, 30,34,38,-tetracontadecaenyl)-5,6-dimethoxy-3-methyl-, (all-E)-(9CI). (CA Index name) / p-Benzoquinone,2-(3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38,-tetra- contadecaenyl)-5,6-dimethoxy-3-methyl- / 2,3-Dimethoxy-5-methyl-farnesylfarnesylgeranyllinaloyl-1,4-benzoquinone.

COMMON NAME	:	Ubiquinone 50, coenzyme Q-199, ubidecarenone, ubiquinone 10, NSC-140865, Adelir, Caomet, Dec afar, Decorenone, Dymion, Heartcin, Inokiton, Iuvacor, Mitocor, Neuquinon, Taidecanone, Ubifact or, Ubiquasar, Ubisan, Ubivis, Ubiten, Udekinon (Ref. 0001) / Bio-quinone, Neuquinone, Ubiquinone Q₁₀.
SYMBOL	:	Co Q₁₀
FORMULA	:	C₅₉H₉₀O₄ MOL.WT (average) : 863.344

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BIOLOGICAL ACTIVITY

The effect of coenzyme Q(Co Q) homologues on the beating of myocardial cells was investigated in cultured cell sheets from mouse fetuses and quail embryos. Myocardial cell sheets grown in Eagle's minimum essential medium with fetal bovine serum showed very weak and irregular beating when this serum was removed from the medium. However, the depressed beating rate and amplitude recovered almost complete within a few minutes by adding CoQ₁₀ to the medium , and the effect of CoQ₁₀ continued over 1 h. CoQ₉ showed a cardiostimulatory effect similar to that of CoQ₁₀.(Ref. 0013)

PHYSICAL AND CHEMICAL PROPERTIES

MELTING POINT	:	49C(Ref. 0028)

BOILING POINT	:

REFRACTIVE INDEX	:

OPTICAL ROTATION	:

DENSITY	:

SOLUBILITY	:

SPECTRAL DATA

UV SPECTRA	:	lmax 270 mm, E¹^%₁_c_m = 176 in petroleum ether(Ref. 0037) [Spectrum 0001] (Ref. 0037)

IR SPECTRA	:	[Spectrum 0002] (Ref. 0037) [Table 0001] (Ref. 0037)

NMR SPECTRA	:	[Spectrum 0003] (Ref. 0037) [Table 0002] (Ref. 0037)

MASS SPECTRA	:

OTHER SPECTRA	:	TLC : Rf = 0.47, hexane and ether (3.5 : 1)(Ref. 0030)

CHROMATOGRAM DATA

A convenient and reliable liquid chromatographic (LC) method with electrochemical detection (ED) was developed for the determination of reduced (ubiquinol) and total ubiquinones in biological materials. After extraction of samples with n-hexane, ubiquinol was separated on a reversed-phase column and assayed directly by ED. In order to determine the total amount of a ubiquinone in biological samples, the ubiquinone was converted into the corresponding reduced form by treatment with sodium borohydride. No significant interfering peak (plastoquinol-9, ubichromenol-9, etc.) was observed in the elution areas of ubiquinol-7 to -11. This LC-ED method was about 70 times more sensitive than the previous LC-UV method and was able to detect 150 pg of ubiquinol-10. The method was applied satisfactorily to the determination of the contents of ubiquinol homologues in biological materials.
The content of ubiquinols is a major component of the total ubiqinones in human plasma and urine and rat plasma and liver, but a minor component in rat heart and kidney. (Ref. 0026)

SOURCE

A comparison of nine different mammalian species, namely mouse, rat, guinea pig, rabbit, pig, goat, sheep, cow, and horse, which vary from 3.5 to 46 years in their maximum longevity indicated that the rate of O₂^- generation in cardiac submitochondrial particles (SMPs) was directly related to the relative amount of CoQ₉ and inversely related to amount of CoQ₁₀, extractable from their cardiac mitochondria. To directly test the relationship between CoQ homologues and the rate of O₂^- generation, rat heart SMPs, naturally containing mainly CoQ₉ and cow heart SMPs, with high natural CoQ₁₀ content , were chosen for depletion/reconstitution experiments.
[Table 0003] (Ref. 0011)
A systematic study for detecting the ubiquinone content in subcellular compartments, cells, and whole-tissue homogenates by a standardized HPLC method performed after an extraction procedure identical for all samples.
It was confirmed that the major coenzyme Q homologue in rat tissues is coenzyme Q₉; however, it was pointed out that all the rodents samples tested contain more than one coenzyme Q homologue. The coenzyme Q homologue distribution is tissue dependent with relatively high coenzyme Q₁₀ content in brain mitochondria, irrespective of the rat strain used. There is no constant relationship of the coenzyme Q content in mitochondria and microsomes fractions. Most organisms tested (including other mammals, bird and fish specimens) have only coenzyme Q₁₀ , while the protozoan Tetrahymena pyriformis contains only coenzyme Q₈.(Ref. 0027)
[Table 0004] (Ref. 0027)
[Table 0005] (Ref. 0027)
[Table 0006] (Ref. 0027)
[Table 0007] (Ref. 0027)
[Table 0008] (Ref. 0027)

CHEMICAL SYNTHESIS

Three and one-half grams of 2,3-dimethoxy-5-methylhydroquinone , 14 g of farnesyl - farnesylgeranylgeraniol, and 2.5 g of anhydrous zinc chloride are reacted as described under ubiquinone-9 (VCQ0002). The crude quinone (12.3 g) [ultraviolet maximum at 270 nm ( Three and one-half grams of 2,3-dimethoxy-5-methylhydroquinone , 14 g of farnesyl - farnesylgeranylgeraniol, and 2.5 g of anhydrous zinc chloride are reacted as described under ubiquinone-9 (VCQ0002). The crude quinone (12.3 g) [ultraviolet maximum at 270 nm (Ed¹^%₁_c_m = 52)] is chromatographed on aluminum oxide to give several fractions possessing EEd¹^%₁_c_m =100-142 (2.8 g). Further purification by recrystallization from alcohol or by rechromatography on polyethylene powder yields pure ubiquinone-10(VCQ0001), m.p. 49

. Ultraviolet absorption maximum at 270 nm (Ed¹^%₁_c_m =173) (in petroleum ether, b.p.80- 105

). Conditions for paper chromatography are the same as described under ubiquinone-9(VCQ0002). (Ref. 0002)

METABOLISM

The pharmacokinetics of coenzyme Q₁₀ (Co Q₁₀) in man was studied by utilizing deuterium-labelled coenzyme Q₁₀(d₅-Co Q₁₀). The absence of an isotope effect in the disposition of d₅-CoQ₁₀ in man was confirmed from the plasma concentration time curves after simultaneous oral dosing of d₅-CoQ₁₀ and unlabelled CoQ₁₀. After oral administration of 100 mg of d₅-CoQ₁₀ to 16 healthy male subjects, the mean plasma Co Q₁₀ level attained a peak of 1.004

0.370 mg/ml at 6.5

1.5 h after administration, and the terminal elimination half-time was 33.19

5.32 h. In most of the subjects, plasma d₅-CoQ₁₀ showed a second peak at 24 h after dosing. (Ref. 0009)

GENETIC INFORMATION

The biosynthesis of ubiquinone was studied in an isolated perfused beating heart preparation from adult male rats to determine rate-limiting steps in the biosynthetic pathway. The isolated hart could incorporate p-hydroxy [U-14C]benzoate into ubiquinones (ubiquinone-9 (VCQ0002) and -10 (VCQ0001)) and two other lipids which were identified as 3-nonaprenyl 4-hydroxybenzoate and 3-decaprenyl 4-hydroxybenzoate. No other their lipids could be detected. Addition of unlabeled mevalonolactone to the perfusate stimulated the rate of incorporation of p-hyudroxy [U-14C]benzoate into 3-nonaprenyl 4-hydroxybenzoate and 3-decaprenyl 4-hydroxybenzoate. The level of radioactivity in these intermediates was much greater than that in ubiquinone-9 and -10.
These results show that in the intact heart there is a larger excess capacity of form postmevalonate isoprenoid precursors of ubiquinone and suggest a possible regulatory step at the premevalonate level. Moreover, the accumulation of prenylated derivatives of 4-hydroxybenzoic acid indicates further rate limitation at one or more the subsequent steps in conversion of these intermediates to ubiquinone.(Ref. 0024)

NOTE

REFERENCES

[0001]

AUTHOR	:	Anonym. (1996) Menadione in The Merck Index , 12th edition (Budavari, S., O'Neil, M. J., Smith, A., Heckelman, P.E., and Kinneary, J., F., eds), pp1679Merck & Co., Inc., Whitehouse Station, N. J.
TITLE	:
JOURNAL	:	The Merck Index
VOL	:	Ubiquinones PAGE : - ()

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[0002]

AUTHOR	:	Mayer,H., and Isler, O.
TITLE	:	Synthesis of ubiquinones
JOURNAL	:	Methods in Enzymology
VOL	:	18 PAGE : 182 -213 (1971)

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[0009]

AUTHOR	:	Tomono, Y., Hasegawa, J., Seki, T., Motegi, K., and Morishita, N.
TITLE	:	Pharmacokinetic study of deuterium-labelled coenzyme Q10 in man PubMed ID:3781673
JOURNAL	:	Int J Clin Pharmacol Ther Toxicol.
VOL	:	24 PAGE : 536-541 (1986)

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[0011]

AUTHOR	:	Lass, A., Agarwal, S., and Sohal, R. S.
TITLE	:	Mitochondrial ubiquinone homologues, superoxide radical generation, and longevity in different mammalian species PubMed ID:9235911
JOURNAL	:	J Biol Chem.
VOL	:	272 PAGE : 19199-19204 (1997)

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[0013]

AUTHOR	:	Kishi, T., Okamoto, T., Takahashi, T., Goshima, K., and Yamagami, T.
TITLE	:	Cardiostimulatory action of coenzyme Q homologues on cultured myocardial cells and their biochemical mechanisms PubMed ID:8241709
JOURNAL	:	Clin Investig.
VOL	:	71 PAGE : S71-75 (1993)

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[0024]

AUTHOR	:	Yamamoto, T., Shimizu, S., Sugawara, H., Momose, K., and Rudney, H.
TITLE	:	Identification of regulatory sites in the biosynthesis of ubiquinone in the perfused rat heart PubMed ID:2916849
JOURNAL	:	Arch Biochem Biophys.
VOL	:	269 PAGE : 86-92 (1989)

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[0026]

AUTHOR	:	Okamoto, T., Fukunaga, Y., Ida, Y., and Kishi, T.
TITLE	:	Determination of reduced and total ubiquinones in biological materials by liquid chromatography with electrochemical detection PubMed ID:3215946
JOURNAL	:	J Chromatogr.
VOL	:	430 PAGE : 11-19 (1988)

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[0027]

AUTHOR	:	Battino, M., Ferri, E., Gorini, A., Federico Villa, R., Rodriguez Huertas, J. F., Fiorella, P., Genova, M. L., Lenaz, G., and Marchetti, M.
TITLE	:	Natural distribution and occurrence of coenzyme Q homologues PubMed ID:2135303
JOURNAL	:	Membr Biochem.
VOL	:	9 PAGE : 179-190 (1990)

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[0028]

AUTHOR	:	Crane, F. L., and Barr, R. (1985) Chemical structure and properties of coenzyme Q related compunds, in Coenzyme Q (Lenaz, G., ed), pp1-37, John Wiley & Sons Ltd.
TITLE	:
JOURNAL	:
VOL	:	PAGE : - ()

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[0030]

AUTHOR	:	He, D. Y., Yu, L., and Yu, C. A.
TITLE	:	Protein ubiquinone interaction. Synthesis and biological properties of 5-alkyl ubiquinone derivatives PubMed ID:7961719
JOURNAL	:	J Biol Chem.
VOL	:	269 PAGE : 27885-27888 (1994)

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[0037]

AUTHOR	:	Sommer,P., and Kofler,M.
TITLE	:	Physicochemical Properties and Methods of Analysis of Phylloquinones, Menaquinones, Ubiquinones, Plastoquinones, Menadione, and Related Compounds. PubMed ID:5340867
JOURNAL	:	Vitamins and Hormones
VOL	:	24 PAGE : 349 -399 (1966)

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