Catalysts of Lipid Oxidation

Catalysts of Lipid Oxidation

Iron The most important nonenzymic catalyst for initiation of lipid peroxidation The most abundant transitional metal in biological systems Possibility of various oxidation states (from –II to +VI), the forms of Fe(II) and Fe(III) is dominated in biological systems

Role of iron and other metal ions in converting less reactive to more reactive species O2- + H2O2 + Fe -----> .OH

(Iron-catalyzed Haber-Weiss reaction)

Lipid peroxides (ROOH) -----> ROO., RO., cytotoxic aldehydes (4hydroxyl-2,3-trans-nonenal, malondialdehyde) Thiols (RSH) + Fe/Cu + O2 -----> O2-, H2O2, .OH, thiyl (RS.) + O2 -----> thiyl peroxyl (RSO2.), RSO. (sulfenyl) NAD(P)H + Fe/Cu + O2 -----> NAD(P)., H2O2, O2-, .OH Ascorbic acid + Fe/Cu -----> semidehydroxy ascorbate radical, H2O2, .OH Catecholamines, related autoxidazable molecules Fe/Cu + O2 -----> H2O2, O2-, .OH, semiquinones

Structural Iron

Hb: 2/3 of total body iron Mb: muscle pigment. Most abundant heme pigment in meat Cytochrome c: electron transport chain Catalase: antioxidant enzyme

Heme Irons Ferrous heme pigment Ferric heme pigment Ferryl complexes Hematin Heating or addition of H2O2 caused the release of heme iron due to oxidative cleavage of porphyrin ring of heme

Formation of reactive species by interaction of Hb with H2O2 Hemoglobin access H2O2 (Ferryl?)

Stimulation of lipid peroxidation

heme degradation

iron ion release

H2O2 .OH

other tissue damage

Hematin Is released from myoglobin before the release of free ionic iron in the presence of H2O2 Hematin can catalyze lipid peroxidation more efficiently than ionic iron because hematin is more reactive than hemeproteins and ferrous ion Is hydrophobicity allows it to permeate into membrane easily. Hematin monomer and hematin with hypervalent iron (FeIV=O) can initiate lipid oxidation.

Storage and Transport iron - Tightly bound iron - Ovotransferrin - Ferritin - Homosiderin

Loosely Bound Iron low molecular weight chelators 2.4~3.9% of total iron Depending on animal species and muscle types Concentration can be influenced by heating, the presence of ascorbic acid and H2O2 and storage Organic phosphate esters (e.g. NAD(P)H, AMP, ADP, and ATP) Inorganic phosphates Amino acids Organic acids (e.g. citrate)

Free Ionic Iron Plays an important role in the catalysis of lipid peroxidation Fe(III) catalyzed lipid peroxidation only in the presence of ascorbic acid Hydrogen peroxide (H2O2) and ascorbate can release free iron from heme pigments and ferritin Transferrin- and ferritin-bound irons nor heme pigments had any catalytic effect in raw muscle.

Biological iron complexes and their possible participation in oxygen radical reactions

Type of iron complexes Loosely bound iron Iron ion attached to phosphate Esters (ATP etc.) Carbohydrates and organic acids (e.g., citrate, deoxiribose) DNA Membrane lipids Mineral ores (asbestos, silicates)

Decomposition of lipid peroxides to form alkoxyl and peroxyl radicals

Hydroxyl radical formation by Fenton chemistry

Yes

Yes

Yes

Yes

Probably yes Yes Yes

Yes Yes Yes

Iron tightly bound to proteins Nonheme iron Ferritin (4500 mol Fe/mol protein) Hemosiderin Lactoferrin (2 mol Fe3+/mol protein) Transferrin (2 mol Fe2+/mol protein)

Yes Yes (when iron is released) Weakly (when iron is released) Weakly (whe iron is released) No No No No

Heme iron Hemoglobin Myoglobin Cytochrome c Catalase

Yes (when iron is released) Yes (when iron is released) Yes (when iron is released) Weakly

Yes Yes Yes Not

(when iron is released) (when iron is released) (when iron is released) observed

Products of Lipid Oxidation

Products of Lipid Oxidation

Oxidation of diene lipids

Oxidation of triene lipids Autoxidation 9-OOH D10,12,15 (37%)

Photo-oxidation 9-OOH D10,12,15 (23%) 10-OOH D8,12,15 (13%)

12-OOH D9,13,15 (8%)

12-OOH D9,13,15 (12%)

13-OOH D9,11,15 (10%)

13-OOH D9,11,15 (14%) 15-OOH D9,12,16 (13%)

16-OOH D9,12,14 (45%)

16-OOH D9,12,14 (25%)

Oxidation of triene lipids

Oxidation of highly unsaturated lipids

Oxidation of highly unsaturated lipids

Secondary Peroxidation Products from Fatty Acids

Hydrocarbons: Alkanes and Alkenes C8-OOH oleate Homolysis

Homolytic beta-scission of a carbon bond on either side of the O-containing carbon atom

Addition

Alkanes, Alkenes C8-hydroperoxide of oleic acid (8-OOH oleate): 1-decene C9-hydroperoxide of oleic acid (9-OOH oleate): 1-nonene C10-hydroperoxide of oleic acid (10-OOH oleate): 1-octene C13-hydroperoxide of linoleic and arachidonic acid: pentane produce pentane C13-hydroperoxide of linoleic acid produces ethane and ethylene

Aldehydes From C8-OOH oleate A CH3(CH2)7CH=CH-CH-(CH2)6-COOH O.

Aldehydes from n-6 fatty acids Peroxidation of n-6 fatty acids (linoleic and arachidonic acid): 9-hydroperoxy linoleate: 2,4-decadienal, and 3-nonenal 13-hydroperoxy linoleate: hexanal and pentanal 10-hydroperoxy linoleate: 2-heptenal Other volatile aldehydes formed: 2-hexenal, 2-octenal, 2,4nonadienal, 4,5-hydroxydecenal, 4-hydroxy-2,3-transnonenal

4-HNE formation 13-hydroperoxy linoleic acid (13-HPODE) Reduction H-abstraction

isomerization oxidation cleavage

4-Hydroxy-2,3-trans nonenal (4HNE)

Formed by linoleate, arachidonic acid oxidation Have high cytotoxicity at high concentrations Inhibits DNA and protein synthesis and generate oxidative stress Act in defense against fungi in plants At low concentrations, have chemotactic effect, stimulate guanylate cyclase and phospholipase C activities

Aldehydes from n-3 fatty acids Peroxidation of n-3 fatty acids (linolenic and EPA, DHA): Various compounds depending upon the location of hydroperoxy group 9-OOH linolenate: 2,4,7-decatrienal, 3,6-nonadienal 12-OOH linolenate: 2,4-heptadienal, 3-hexenal 13-OOH linolenate: 3-hexenal and 2-pentenal 16-OOH linolenate: propanal Other volatile aldehydes formed: butanal, 4,5-epoxy hepta2-enal, 4-hydroperoxy hexenal, 4,5-hydroxydecenal, 4hydroxy-2,3-trans-hexenal

Malonaldehyde Formed by further degradation of hydroperoxy aldehydes The main precursor: monocyclic peroxides formed from fatty acids with 3 or more double bonds Introduces cross-links in proteins and induces profound alteration in their biochemical properties

Epoxides (or Oxirane oxygen)

Linoleic epoxides

Epoxides

Generated by the attack of any double bonds present in fatty acid chain by a lipid peroxyl radical (ROO.) Toxic Some of them (epoxyeicosatrienoic acid) affects blood flow, mitogenesis, platelate aggregation, anti-inflamatory, vasoregulation (relax renal arteries)

Volatile compounds produced from arachidonic acid 1-Pentene Pentane 1-Methoxy-2-methyl-1-propene 2-Methyl pentane 3-Methyl pentane 2,2-Dimethyl pentane 2,3-Dimethyl pentane 3,3-Dimethyl pentane 1-Hexene Hexane 2-Methyl hexane 3-Methyl hexane 3-Ethyl hexane 2,4-Dimethyl hexane 1-Octene Octane 2-Octene 3-Octene 3-Methyl octane 2,6-Dimethyl octane 1-Heptene Heptane 2,6-Dimethyl heptane 1,2,4-Trimethyl heptane Ethyl benzene 1,3-Dimethyl benzene 2,2,3-Trimethyl butane 3-Nonen-1-ol Undecanenitrile Octahydro-1H-indene 1,3-Cyclopentadiene 4-Methyl cyclopentene 3-Methyl cyclopentene Methyl cyclopentane 1,1,3-Trimethyl cyclopentane Cyclohexane Cyclohexene Methyl cyclohexane 1,3-Dimethyl cylohexane Ethyl cyclohexane 1,1,3-Trimethyl cyclohexane 1,2,4-Trimethyl cyclohexane 1,2,3,5-Tetramethyl cyclohexane 1-Ethyl-3-methyl cyclohexane Propyl cyclohexane 1-Ethyl-2,3-dimethyl cyclohexane Butyl cyclohexane 1,1,2,3-Tetramethyl cyclohexane 1-Methyl-4-(1-methylethyl)-cyclohexane 1,1,4-Trimethyl cyclohexane 1,2-Dimethyl cyclooctane