A A c AcvCVch

HaC CH C C N C c CH „ ' ' H, H, H H2 Hj | CHa—C —S SH NH

O Acetylhydrolipoamide


Acetyl-Co A


Flgurr 9,45 Upoamide is a covalently bound prosthetic group of pyruvate dehydrogenase and four other enzymes and 226. These lipoamides serve as acceptors for the acetyl residues from pyruvate, transfer them to acetyl-CoA. and reduce lipoamide to dihydrolipoamide in the process. Another component of ihe complex, dihydrolipoamide dehydrogenase (1:3: ECI.8.I.4) transfers the hydrogens \ia FAD to NAD Ihe same gene encodes the dihydrolipoamide dehydrogenase of pyruvate dehydrogenase and the other two alpha-ketoacid dehydrogenases. The enzyme complex is inactivated by phosphorylation ([pyruvate dehydrogenase (lipoamide)] kinase: EC2.7.1.99) of three serines in the El siihunit and reactivated by removal of these phosphates by [pyruvate dehydrogenase (lipoamide)]-phosphatase (EC3.1.3.43),

2-Oxoglutarate dehydrogenase (EC2.3 1 61): The TC A-cycle intermediate 2-oxoglu-tarate is metabolized to suceinyl-CoA by a large TCP-dependent multienzyme complex containing 24 copies of the lipoamide-contaming subunit K2 (dihydrolipoamide suc-cinyltransferase) with octahedral symmetry: these subunits contain a single lipoamide attached to lysine 110.

Branched-chain alpha-keto acid dehydrogenase ('£€'): The alpha-ketoacids 3-methyl-2-oxobutanoate. 4-methyl-2-oxopentanoate, and (S)-3-methy 1-2-oxopen l anoat c, generated by deamination of the branched-chain amino acids valine, leucine, and isoieucme. are decarboxylated hy another very large TPP-dependent enzyme complex containing multiple lipoamide-containing subunits E2 (3-methyl-2-oxobtitanoatc dehydrogenase (lipoamide); EC1.2.4.4). The enzyme complex is inactivated by phosphorylation ([3-methy 1-2-oxobutanoate dehydrogenase (lipoamide)] kinase; EC2.7.1.115), and reactivated by dephosphorylation ([3-mcthyI-2-oxobutanoatedehydrogenase (lipoamide)|-phosphalase; F.C3.I.3.52).

Glycine dehydrogenase (EC1.4.4.2): Glycine is decarboxylated in mitochondria by a large pyridoxal phosphate-dependent enzyme complex composed of multiple sub-units P.T. L. and H; the 11 subunit contains lipoamide. In a fashion, similar to the three lipoatC'-dependent alpha-ketoacid dehydrogenases, the lipoamide arm acts as an acceptor for a methylene group from glycine, transfers it to folate, and is reduced in the process. The T subunit then transfers the hydrogen \ ia FAD to NAD, Antiaddation: Dehydrolipoate reduces ubiquinone and semiubiquinone to ubiquinol thereby enhancing the antioxidant potential of ubiquinol and preventing the potent oxidant-free-radical action of the semiquinone (Kozlov el al.. 1999). Since the mitochondrial oxidation of pyruvate, a Ipha-ketog I utarate. branched-chain alpha-keto acids, and glycine continuously regenerates oxidized lipoate, there is a constant suppW of antioxidant dehydrolipoate. The high iron and copper-binding potential of lipoate also reduces the risk of oxygen-free radical producing Fenton reactions. Lipoate can function as an oxygen free radical scavenger and decrease LDL oxidation and the production of F2-isoprostanes (Marangon et al.. 1999). The mitigation of neuroleptic action (haloperidol) may be due to protection of enzymes (mitochondrial complex I) from oxidation (Balijepalli et al., 1999). Another important mechanism whereby lipoate protects against toxic effects of cisplatin and other compounds may be the maintenance of reduced glutathione concentrations and inhibiting lipid peroxidation. As with other antioxidants, lipoate may become a pro-oxidant under some conditions (Mottley and Mason, 2001), and the potential risks of large supplemental doses remain to be evaluated.

Glucose metabolism: Lipoate increased insulin sensittv ity (Jacob etal., 1999) and cellular glucose uplake, Improvement of glucose transport may be the mechanism underlying the prevention of polyneuropathy by lipoatc administration in an animal model (Kishi el ul., 1999). A protective effect against diabetic embryopathy (neural tube defect) anil vascular placenta damage has been suggested (Wiznitzer et ul., 1999). Liver protection Upoic acid has been used with some success in the mitigation of the effects of amanita poisoning, it may also protect hcpatocytes through the activation of uroporphyrinogen decarboxylase (EC4.1.1.7, Vilas et al., 1999). Acetylcholine: Dihydrolipoie acid is a powerful activator of choline O-acety I transferase (EC2.3.1.6) and may have an important regulatory effect on the synthesis of acetylcholine.

Other effects: Depletion ofCoA may impair glycine con jugation of benzoic acid by LA possibly compromising the tubular secretion of bcnzoylglyeine and causing acute renal failure in an animal model of benzoic acid exposure (Circgus el ul.. 1446).


BaltjepalH S. Boyd MR. Ravindranath V Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation. Neumfthurmaeal 1999^8:567 77 Breithaupt-Grogler K. Niebcli G. Schneider L. Erb K. Hermann R. Blume till. Sehug BS. Belz GG. Dose-proportionality of oral thioctic acid coincidence of assessments via pooled plasma and individual data. Eur J Pharmaceut Sci I999;8:57 65 Fujiwara K. Suzuki M, Oku mac hi Y. Okamura-lkeda K. Fujiwara T. Takahashi E. Motokawa Y. Molecular cloning, structural characterization and chromosomal localization of human I ipoy I transferase gene. Eur J Binchem 1999;260:76) 7 Circgus Z. l ekete T. Halaszi E, Klaassen CD. Lipoic acid impairs glycine conjugation of benzoic acid and renal excretion of benzoy¡glycine. Drug Melab Dtsp 1496;24:682 8 Haramaki N. I lan D, I landelman GJ, Tritschlcr HJ. Packer L. Cytosolic and mitochondrial systems for NADU - and NADPH-dependent reduction ofalpha-ltpoic acid. Free Rati Biol Med 1997;22:535-42 Jacob S. Ruus P. Hermann R. Tritschlcr 11.1. Maerker E. Renn W, Augustin 1IJ. Dietze GJ. Rett K. Oral administration of RAC-aIpha-lipoic acid modulates insulin sensitivity in patients with lype-2 diabetes mellitus: a placebo-controlled pilot trial. Free Rod Biol Med 1499;27:309 14 Jordan SW, Cronan JE Jr. A new metabolic link. I he acyl carrier protein of lipid synthesis donates lipoic acid to the pyruvate dehydrogenase complex in Escherichia coli and mitochondria../ Bud Chem 1447:272:17903-6 Kishi Y, SchmelzerJD.YaoJK,tollman PJ. Nickander KK. Tritschlcr HJ, Low PA. Alplta-lipoic acid: effect on glucose uptake, sorbitol pathway, and energy metabolism in experimental diabetic neuropathy. Diabetes 1999:48:2045 51 Kozlov AV. Gille L, Staniek k. Nohl H, Dihydrolipoie acid maintains ubiquinone in the antioxidant active form by two-electron reduction of ubiquinone and one-electron reduction of ubisemiquinone inh Biochem Biophvs I999;363:148 54 Marangon K. Devaraj S. Tirosh O. Packer L, Jialal 1 Comparison of the effect of alpha-lipttic acid and alpha-tocopherol supplementation on measures of oxidative stress. Free Rod Bio! Med 1499:27; 1114 21

Mottiey t\ Mason RP Sull'ur-cemered radical formation from the antioxidant dihydro-

lipoic- acid. J Biol Chem 2001:276:42677-83 Peinado J. Sies H, Akerboom I P Hepatic lipoate uptake. Arch Biochem Biophys 1989; 273:389-95

Prasad PD. Wang H. Kekuda K. Fujita T. Fei YJ. Devoe I I). Leibach FH, Ganapathy V Cloning and functional expression of a cDNA encoding a mammalian sodium-dependeni vitamin transporter mediating the uptake of pantothenate, biotin. and lipoate, J Biol Chem 1998:273:7501 -6 Vilas GL, Aldonatti C. San Martin de Viafe LC. Rios de Molina MC. Lffect of alpha lipoic acid amide on hexachlorobenzene porphyria. Biochem Mot Biol hit 1999:47:815-23 Wada II. Shintani I). Ohlrogge J. Why do mitochondria synthesize fatty acids? Evidence for involvement in lipoic acid production. Proc Natl Acad Sci USA 1997:94:1591 Wang H, Huang W, Fei YJ. Xia 11. Yang-Feng FL. Leibach 1 11. Devoe LD, Ganapathy V. Prasad PD. Human placental Na*-dependent multivitamin transporter. Cloning, functional expression, gene structure, and chromosomal localization. J Bio! Chem 1999:274:14875-83

Wi/nit/er A. Ayalon N, Hcrshkovitz R. Khamaisi M, Rcece FA, Trisehlcr H. Bashan N. Lipoic acid prevention of neural tube defects in offspring of rats with strcptozocin-indueed diabetes. Am .1 Ohstct Gynecol 1999; | 80: IXS 93 Ynshikawa K, Hayakawa K. KaLsumata N. Tanaka T. Kitnura T, Yamauchi K. Highperformance liquid chromatographic determination of lipoamidasc flipoyl-X hydrolase) activity with a novel substrate, lipoyl-6-aminoquinoline. J Chrom Biometi. Ipp 1996:679:41-7


The term ubiquinone (coenzyme 0- mitoquinonc. SA. Q-275. 272-substanee) comprises fat-soluble ben/oquinones differing in the length of the isopreny) side chain. The functional compound in humans (ubiquinone-10, coenzyme Q10. Q-199. ubitle-carcnone. 2.3-dimcthoxy-5-mcihyl-6-decaprenyl-l ,4-bcn/oquinone; molecular weight X62) has 10 repealing isopreny] units in the side chain.


CoA coenzyme A

Q10 ubiquinone-10

SAM S-adenosyl methionine


CoA coenzyme A

Q10 ubiquinone-10

SAM S-adenosyl methionine

Figure 9.46 Ubiqumone-tO

Figure 9.46 Ubiqumone-tO

Nutritional summary

Function: Ubiquinone-10 (Q10) is needed lor the electron transport of oxidative phosphorylation, is a cefaclor of pyrimtdine nucleotide synthesis, aids nitric oxide recycling, and acts as an intracellular antioxidant.

Food sources: Most ubiquinone-111 is consumed with meal and poultry, and some germ oils.

Requirements Normally adequate amounts are synthesized endogenously requiring sufficient availability of tyrosine and unrestricted isoprcnyl synthesis. Deficiency Genetically low synthesis can cause muscle weakness, fatigability, mental impairment and seizures (Ogasaharu et id.. 1989: Boitier el a!.. 1998), In some circumstances, such as heart failure and during treatment with HMG-CoA reductase inhibitors (statins), endogenous production may not be adequate, and additional dietary intakes of up to 3Umgd may be beneficial.

Excessive intake: Supplementation with lODmg ubiquinone-10/day has been used for up to six years without adverse effects.

Endogenous sources

Most tissues synthesize QUI from farnesyl diphosphate and tyrosine (Nagata et id., 1990) via a multisiep process that requires vitamin B6, S-adenosyl methionine (methionine, folate. BI2), iron, and magnesium. Daily production is about ]2mg (Flmberger et til.. 19X7), Decreased availability of tyrosine in phenylketonuria lowers (J Id concentrations (Artuch et al., 1999), The relevance of additional dietary deficiencies and metabolic factors remains unclear.

Synthesis of the ring system appears to take place in mitochondria. The side chain is produced in the Golgi system (Appelkvist et al., 1494). Since peroxisomal inducers promote endogenous synthesis, al least some steps may also occur in peroxisomes (Turunen et al.. 2000).

The ring moiety. 4-hydroxybenzoate. is derived mainly from 1.-tyrosine (Artuch et al., 1999). The reactions responsible for the conversion of L-tvrosine to 4-hydro\y ben-zoate have not been characterized yet. Synthesis of the side-chain moiety of coenzyme Q uses farnesyl diphosphate, which is extended in several as yet unresolved steps to octa prenyl diphosphate (solanyl diphosphate). Further extension of the chain to the nonaprenyl. and presumably then to the decaprcnyl, is catalyzed by trans-octaprenyltranstransferasc (EC2.5.I.111. The side chain can then be joined to the ring by 4-hydroxybenzoate nonaprenyl transferase (EC2-5J.39) or a similar magnesium-dependent enzyme. Only a lew of the following steps have been elucidated. 4.5-Dihydroxybenzoate is 5-methylatcd by an enzyme identical or similar to the yeast protein Coq3 (hexaprenyl di hydroxy benzoate methyl transferase, EC2.I.I.114) in an S-adenosyl methionine (SAM (-requiring reaction which might be the rate-limiting step. Synthesis is completed by the fcrroenzyme 3-demethyIubiquinonc-9 3-0-methv I transferase (EC2.I.1.64), which again requires SAM.

n-ROH Isopontenyi

„ noftnpTifiyl

*p-0H ttmhospnats 'OH

I magnesium) G OH

tioCflpWrtyftfl a oh V

OH l-Vfro&m glutaraie


Tyrosine aminotfaft&tera&ft (PLP)


0 OH

4~Hydmxy-phcryipyruvutif ucvojnu' if

4-OHt.cnroela HO,

4- Hydro nyt>evizooie x

ttflnspnenyftf&nsterfese imngnmium)


HouptQnyl ifchydraKybcnroitle nwlhyt '.inrnlrrftir

SDownolhyl QlO


3-Dometnyi f t u&quinora 9


Tig Lira 9.47

(al Endogenous ubiquinone-10, part 1; (b) endogenous ubiquinone-10. part 2

CLK-l (homologue of yeast Coq7pCat5p) is another mitochondrial inner membrane protein directly involved in ubiquinone biosynthesis (Vajo el at., 1999). but its exact function is not yet understood.

Q-methy(transferase catalyzes the SAM-dependent methylation of 3.4-dihydroxy-5-polyprenyl benzoic acid to 3-methoxy-4-hydroxy-5-polyprcnyI benzoic acid and of 2-polyprenyl-3-methyl-5-hydroxy-6-methoxy-1,4 benzoqumol (demethyl ubiquinol) to ubiquinol {Jonassen and Clarke, 2000).

Dietary sources

Additional amounts of QIO are derived from food typically about 3- 5mg per day (Weber el at., 1997), Good sources are meat, poultry, cereals, and com oil (Dupont, 1990: Weber et at., 1997),

Digestion and absorption

Q10 appears to he absorbed intact from the intestine (Weber et a I., 1997). but neither the exact location nor the extent or mechanism is known.

Transport and cellular uptake

Blood circulation: Normal Q10 concentrations in serum are around 0.6 jxmol/1, slightly higher in early childhood (Artuch et at., 1999). Circulating QIO is taken up rapidly front blood into liver, then re-sccretcd with very-low-density lipoprotein (Yuzuriha eta I.. 19X3). The transfer mechanisms into other tissues remains in doubt, however (Turunen ei at.. 1999). Both the oxidized and reduced forms of QIO are a polar and readily permeate mitochondrial and other membranes.

Catabolism and excretion

The steps involved in 010 breakdown and excretion arc not well characterized, yet. Regulation

Little is known about the mechanisms that maintain a constant supply ofQlO. Function

Electron transport: Complex I of the oxidative phosphorylation system is the electron-trans lemng-llavoprotem dehydrogenase (IX1.5.5.1) which catalyzes the electron transfer from primary llavoprotein dehydrogenases in the mitochondrial matrix to QKJ in the inner membrane.

Qlo also participates in electron transport of oxidative phosphorylation from succinate (which is converted to fumaratc) to oxygen at the matrix face of the inner mitochondrial membrane by complex II (succinate dehydrogenase ubiquinone: EC*;

as a result of this oxidation protons are pumped into the intermembiane space for the eventual capturing of this energy by ATP synthase during the flow of proton hack across the intermembrane into the matrix.

At the cyiosolic face the reduced form, ubisemiquinone IQH2), is oxidized by complex III to its semiquinone by transferring an electron \ia an Fe-S cluster to cytochrome cl. and then to (J II) by transferring another electron via b566 to b560. At the matrix face the transfer of two electrons from b560 to QIO reduces this again via the semiquinone to 0112- I his ubiquinone cycle is possible because Q10 and QH2 are uncharged and diffuse freely from one face of the inner mitochondrial membrane to the other.

The importance of QIO for ton transport and ATP production, especially during rapid growth, is underscored by the finding that the viability of embryos depends on adequate QIO availability (Stojkovicetal„ 1999),

Q]0 is also a constituent of a lysosomal electron transport chain The redox potentials carried through this electron transport chain drive the transport of protons across the lysosomal membrane and help to build up the acid environment of lysosomes (Oille and Nohl, 2000).

Redox reactions Ubiquinone is an electron acceptor lor various mitochondrial enzymes such as dihydroorotate dehydrogenase I EC for uridine synthesis.

Another redox reaction involving QIO is the removal of nitrite, the end product of intracellular nitric oxide degradation. A mitochondrial nitrite reductase (no Ft number assigned) uses ubisemiquinone associated with the be I complex to convert the potentially toxic nitrite back to nitric oxide thus providing an alternative source for this signaling compound which is independent ofarginine (Kozlov. Staniek etui. 1999). Ubiquinol also acts as a general intracellular antioxidant (l .rnster and Dallner. 1995). In these various reactions the reduced form ubiquinote is oxidized to ubiquinone or to ubisemiquinone which has pro-o.xidant properties itself (Nolil et til., 1999). fhe oxidized forms of QIO can then be reactivated to ubiquinole by diltydrolipoic acid (Kozlov.Gill celal., 1999).

Supplement use: Contrary to common expectations dietary supplements did not improve aerobic power in healthy people (Uonctti etui., 2(KH>), nor was ejection fraction, peak oxygen consumption, or exercise duration increased in patients with congestive heart failure receiving standard medical therapy (Khatta et a I., 2000).


Appelkvist EL. A berg F. Guan Z. Parmryd 1. Dallner G, Regulation of coenzyme Q

biosynthesis. MolAsp Med l994:15:S37-^(> Artuch R. Vilaseea MA, Moreno J. Lambruschini N. Cambra FJ, Campistol J. Decreased serum ubiquinone-10 concentrations in phenylketonuria. Am J Clin Nutr 1999;70:892-5 Bonetti A. Solito F. Carmosino G, Bargossi AM. Fiorella PL. Effect of ubidecarenone oral treatment on aerobic power in middle-aged trained subjects. J Spurts Med Pins Fitness 2000:40:51-7

Boitier E, Degoul F. Desguerre 1. Charpentier C. Francois D, Ponsot (i. Diry M. Rustin P. MarsacC, A case of mitochondrial eneephalo myopathy associated with a muscle eoen-zyme Q10 deficiency../ Neurol Sci 1998:15f>:41 -6

Dupont J, White PJ. Carpenter V1P. Schacfer EJ, Mcydani SN, Elson CE. Woods M, Gorbach SL. Food uses and health cffects of corn oil. 7,4 m CollNutr I990;9:438 70 Elmberger P(.i. Kalen A. Appelkvist EL. DallnerG. In vitro and in viva synthesis of do lie hoi and other main mevalonate products in various organs of the rat. Eur J Biochem 1087; 168:1 II

Ernsler L. DallnerG. Biochemical, physiological and medical aspects of ubiquinone function, Biochim Biophv.tActa I 495:1271:195-204 Gille L. Nohl II. The existence of a lysosomal redox chain and the role of ubiquinone.

Arch Biochem Biophys 2000;37S:347 54 JonassenT. Clarke CF. Isolation and functional expression of human COQ3. a gene encoding a methyl transferase required for ubiquinone biosynthesis. J Biol Chem 2000; 275:12381-7

Khatta M, Alexander BS, Krichten CM, Fisher ML, Freudenberger R. Robinson SW, Gottlieb SS, The effect of coenzyme QUI in patients with congestive heart failure. Ann fm Med 2(100; 132:636-40 Kozlov AV, Gille L. Staniek K. Nohl H. Dihydrolipoie acid maintains ubiquinone in the antioxidant active form by two-electron reduction of ubiquinone and one-electron reduction of ubisemi qui none. Arch Biochem Biophys 1090363:148-54 Ko/lov AV, Staniek k. Nohl H. Nitrite reductase activity is a novel function of mammalian mitochondria. ¡ LBS Lett 1949:454:127-30 NagataY, I lidaka Y, Ishida F. Kamci T. I Heels of simvastatin (MK-733) on branched pathway of mevalonate. Japn J Pharmacol 1990;54:315-24 Nohl H, Gille I, Ko/lov AV. Critical aspects of die antioxidant function of coenzyme Q in bio membranes. Bio/actors I999;9:I55 61 Ogasahara S. F.ngel AG, Frens D. Mack D. Muscle coenzyme Q deficiency in familial mitochondrial cncephalomyopathy. Proc Natl Acad Sci I SA 14X9:86:2379 82 Stojkovic M. Westesen K. Zakhartchenko V, Stojkovie P, Boxhammcr K. Wolf E. Coenzyme Q( 10) in submicron-sized dispersion improves development, hatching, cell proliferation. and adenosine triphosphate content of in vitru-produced bovine embryos, Biol Reprod 1999;61:541-7 Turunen M. Appelkvist EL, Sindelar P. DallnerG. Blood concentration of coenzyme Qt 10)

increases in rats when estcrilied forms are administered. J Nutr 1499:124:2113 18 Turunen M, Peters JM. Gonzalez I J, Schcdni S, Dallner G. Influence of peroxisome proliferator-aetivated receptor alpha on ubiquinone biosynthesis. J Mol Biol 2000:247:607-14

Vajo /_. King LM. Jonassen T, Wilkin DJ. I lo N. Munnich A. Clarke CF, Francomano CA, Conservation of the Caenorhabdilis elcgans timing gene elk-1 from veast (o human: a gene required lor ubiquinone biosynthesis w ith potential implications for aging, Mamm Genome 1999;10:1000-4 Weber C, Bystcd A, Holmer ii. Coenzyme 010 in the diet - daily intake and relative bioavailability. Mai Asp Med 1997;I8:S25I-S254 Vu/urihaT, fakada M. Katayama k. Transport of [ 14C jcoenzy me Q10 from the liver toother tissues after intravenous administration tit guinea pigs, Biochim Biophys Acta 1983; 754:286-91

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