AAAnvW

O ley I-CoA

Figur* 6.9 Chain elongation and desaturation

These activities add in sum with each cycle a malonyl-CoA to the growing chain, oxidize two NADP1I molecules to NADP. and release one carbon dioxide molecule and a free coenzyme A molecule,

Cham elongation The length of fatly acids with 12, 14 or 1 (i carbons can be extended in the cytosnl by the addition of 2-carbon units (Moon et ui. 2001). The first step is the conjugation to coenzyme A by long-chain-fatty-acid-C'oA ligase (EC6.2.1.3). A specific NADI 1-using long-chain fatty acyl eiongasc (no EC number assigned) adds malonvl-CoA to theacyl-CoA and releases carbon dioxide and free Co A. This and presumably additional related enzymes are active mainly in hepatocytcs. adipocytes, and in mammary glands during lactation.

Desaturation: Several enzyme systems can introduce double bonds at specific sites of a well-defined range of fatty acvl-CoAs. The ferroenzyme stearyl-CoA desaturase (dclta-9 desaturase, ECU4,99.11, which is attached through a myristate anchor to the cytoplasmic side of the endoplasmic reticulum, uses cytochrome b5 and oxygen to introduce a double bond at carbon 9 of acyl-CoAs with chain lengths between 14 and IS, FMN- and FAD-contairiing cytochrome H5 reductase (EC1.6.2.2) then reactivates this electron donor in an NADU-dependent reaction.

A distinct linoleoyl-CoA desaturase (delta-6 desaturase, EC1.14.49.25) acts on I S:2n-6, l&:3n-3,24:4n-6 and 24:5n-3 (deAntucno et ul.. 2001). 1 his ferroenzyme uses the cytochrome b5 system like other desaturases.

Delta-4 and delta-5 desaturating systems also exist, but are less well characterized.

Dietary sources

The bulk of dietary fatty acids is consumed as triglycerides, smaller amounts are taken up with di- and monoglycerides. phospholipids, and cholesteryi esters: plasmalogens, glycolipids, and other complex compounds contribute relatively little in a mixed diet. Fatty acid composition is greatly dependent on the type of food and its origin. Almost all of them have an even number of carbons. Small amounts ofpentadecanoic acid come with dairy foods (Wolk et ul.. 2001) and peanuts. The intake of heptadecanoic acid and other odd-chain fatty acids is even less. W hile oleic acid (octadec-c9-enoic acid) is the main isomer in most foods, several other forms are consumed in small amounts. One of these, petroselinic acid (oeladec-c6-enoic acid), is even the major form in the seed oil of coriander and other Umbellijerae species. Transvaccenic acid (octadec-t 11 -enoic acid) is a naturally occurring minor constituent of ruminant fat and may contribute some health benefits as a precursor of conjugated linoleie acid (CI. A). The other trans fatty acids in foods, in contrast, arise from partial hydrogenation of polyunsaturated fatty acids and are associated with unfavorable health outcomes, l-rucic acid (docosa-cl3-enoic acid) is another monoenic fatty acid of ill repute, due to concern that it might cause cardiac lipidosis and other harm. Genetic plant modification has reduced the content in rapeseed oil. the main source, from more than 40% to a few percent and led to the renaming ('canola' oil) of the new product.

Plant foods tend to contain more long-chain mono- and polyunsaturated acids and short- and medium-chain fatty acids. Animal foods usually have more saturated long-chain fatly acids, many exceptions notwithstanding. Dairy foods provide most of the myristic acid in the diet, plant oils most of the linolcic acid and linotcnic acid, and cold-water fish most of the eicosapcntadccacnoic acid and docosahcxacnoic acid. Some edible marine algae, such as ( ndaria pimifida and i 'Iva pertusa, contain the unusual omega-3 fatty acid hexadeca-4,7,10,l3-tetraenoic acid. Blackcurrant seeds are a rare plant source (2 4%) of stcaridonic acid (octadeca-6.9,12,15-tetracnoic acid).

Phospholipids and cholesterol esters tend to have a higher proportion of long-chain polyunsaturated fatty acids than triglycerides. Game animals (e.g. wild boar) living in the wild have much leaner meat than closely related domesticated animals and more polyunsaturated than saturated fatty acids.

The heating of unsaturated fats, such as during deep-frying, causes oxidation. A conjugated diene content of 4-20% has to be considered normal in such foods and may be higher (Staprans et ul.,

The smaller (any acids are volatile and tend to have strong odors, such as is the case with butyric acid. Lipases from specilic bacteria release odorous fatty acids from triglycerides in chccses, for instance, and give them their characteristic aroma. The compound responsible for the typical odor in goat s milk products is thought to be 4-ethyloctanoate (Alonso et al., 1999), Dairy products are also the major source of a wide range of branchcd-chain fatty acids such as iso-C 15:0 and iso-C 17:0 (derived from leucine metabolism). antciso-C 15:0 and anteiso-Cl7:0 (from isoleucine). and iso-C*16:0 (from valine). Human milk contains nearly forty different fatty acids, including the branchcd-chain fatty acids mentioned.

Digestion

Di- and triglycerides are hvdrolyzed by several lipases in the upper digestive tract. Corresponding to their target environment they differ in pi I optimum and cofactor requirements. Lingual lipase is active at neutral to alkaline pi I white gastric lipase (also secreted with milk) tolerates the acidic environment of the stomach; neither is dependent on further cofactors. Mixed micelles arc generated upon mixing of bile acids and phospholipids from bile with dietary triglycerides, and stabilized by the addition of monoglyccrides from ongoing triglyceride hydrolysis. Bile-salt activated lipase (EC3.I.K3) from pancreas efficiently hydrolyzes mixed micelles at the alkaline pfl typical of small intestine. The enzyme from pancreas acts in concert w ith a colipase, which allows the lipase to penetrate the bile acid coating of mixed micelles and interact with the glycerides inside. This lipase also has carboxyiester lipase (UC3.1.1.13) activity and cleaves fatly acids off cholesterol esters. Phospholipa.se A2 (EC3,1.1.4) from pancreas cleaves off the middle fatty acid (position sn-2).

Absorption

Free acids and monoglyccrides from mixed micelles transfer into cnierocytes of the small intestine by di (fusion and facilitated transport. A wide range of fatty acids is taken up. including branchcd-chain and oxidized (dienic) fatty acids.

Long-chain fatty acids tend to be conjugated to C'oA by one of several specific long-chain fatty acid CoA lipases. Most of the acyl-CoA is used for triglyceride synthesis (for pathways see below, under Storage); a much smaller proportion contributes to the synthesis of cholesterol esters, phospholipids, and other complex lipids. Some acyl-CoA undergoes beta-oxidation and is used as an energy fuel for the enterocytes.

Triglycerides arc assembled into chylomicrons w ith cholesterol esters, phospholipids, and one molecule of apolipoprotein B4N per particle, and secreted into intestinal lymphatic vessels. The fatty acid binding proteins 1 and 2, microsomal triglyceride transfer protein (MTP), and presumably additional proteins are necessary for the intracellular transport of fatty acids and subsequent assembly and secretion of chylomicrons (Dannoura et at,. Ingested fat reaches the thoracic duct, packaged into chylomicrons, within HO minutes (Qureshy a ul.. 2001) and is transported from there with lymph into the vena cava.

Free fatty acids (mainly those with 12 or less carbon atoms) also can be transferred directly into portal blood through incompletely understood mechanisms,

A highly specific eytidine deaminase (apolipoprotein B editing catalytic subunit 1. APOBEC-1, no EC' number assigned) is part of a multiprotein complex, which modi-lies eytidine 6666 of the apoB mRNA to uridine and thereby introduces a stop eodon into the sequence. Due to this modification the intestinal protein transcripts are shortened to about 48% of the full-length version (hence B4X). In humans this enzyme is expressed only in small intestine (Cheng a ul., 2001). which means that all intestinal apoB is of'

Insurance Claims Processing Steps

Intestinal lumen m

Intestinal lumen

Brush border membrane

Brush border membrane

Basolateral membrane

Figure 6.10 Intestinal absorption of fit the apoB48 variety. Rodents and many other mammals, in contrast, produce in their enterocytes both apoB48 and the lull-length version, apoBlOO.

Transport and cellular uptake

Blood circulation: Free fatty acids in blood occur almost exclusively bound non-covalenily to albumin. Poslabsorptivc free fatty acids that are carried in portal blood arc taken up into hepatocytes by active transport during their lirst pass through the liver. Skeletal and cardiac muscle cells, and adipocytes, get fatty acids from circulating triglyceride-rich lipoproteins (TRL; chylomicrons and very-low-density lipoproteins, VLDL). Muscle cells of the heart depend for most of their energy on long-chain fatty acids taken up from circulation. Triglycerides inTRL are hydrolyzed by luminal lipoprotein lipase. To be accessible for lipase action TRL have to contain sufficient amounts of the activating peptide apt)lipoprotein CII (apoCII); TRL also contain apolipoprotein CIII (apoCllt) which inhibits lipoprotein lipase (LPL. EC3.1.1.34) activity, thereby pacing the release of fatly acids from TRL. Another 1RL constituent is apolipoprotein CI (apoCI), a small peptide constituent of chylomicron and VLDL remnants. It inhibits binding of lipoproteins to the LDL receptor. LDL receptor-related protein, and the VLDL receptor, slows lipid exchange mediated by the cholcsteryl ester transfer protein and decreases cellular fatty acid uptake (Shachtcr, 2001).

Most lipoprotein processing occurs in blood. Chylomicrons, which carry triglycerides from small intestinal absorption, and VLDL, which transport excess triglycerides from the liver, release much of triglycerides as they pass through small arterioles and arterial capillaries. LPL on the endothelial surface of these vessels cleaves triglycerides within the Lp and the resulting fatly acids and glycerol arc ejected because they are no longer compatible with the lipophilic environment of the lipoproteins. The free fatty acids have a high probability to be released in close proximity to muscle cells, their o vldl remnants t fal'y l-imqtoti.n acids

tatty acids pönal blood

io VLDL

Figure 6.11 Transport of fat from the liver l-imqtoti.n acids

tatty acids io VLDL

pönal blood

Figure 6.11 Transport of fat from the liver primary target. Fatty acids can easily diffuse through the yaps between adjoining endothelial cells ofmusele capillaries into the peri capillary space around muscle cells. At least six distinct fatty acid transport proteins are expressed in various tissues. The uptake of the bulk of free fatty acids into muscle cells and adipocytes depends on the fatty acid transport protein I (FATP-1, CD36. SLC27A1; Martin et at, 2000), either in conjunction with or augmented by plasma membrane fatty acid binding protein (FABPpm; Slorch and Thumscr, 2000) and fatty acid translocase (FAT). Transport across the cell membrane appears to be coupled to acyl-CoA synthase (EC6.2.I.3) activity. Apparently this activity does not always require a separate protein, since FATP4 in adipocytes functions as an acyl-CoA synthetase (Herrmann et til., 2001).

Fatty acids can also be taken up into some cells with the entire TRI. Specific receptors recognize chylomicron remnants (Brown et at.. 2000) and VLDL (Tacken etui.. 2(H)! t.

Fatty acids that remain in circulation bind to albumin. Their main fate is uptake in the liver via a proton-driven fatty acid transporter (Elsing et ul„ I9%>, Blood-brain barrier; Transport of fatty acids from circulation into brain is very limited and highly selective (Edmond. 2001). The mechanism for the specific transfer of essential fatty acids, which are needed for the synthesis of many brain-typical structural compounds, remains unclear. Small amounts may be transported with high-density lipoproteins (HDL), which enter brain capillary endothelium via a HDL-binding receptor (Goti et al.. 2000).

Materno-fetal transfer: The growing fetus is especially dependent on a generous supply of long-chain polyunsaturated fatty acids. About 3 g of docosahexaenoic acid (DMA) has to be supplied every day to a third-trimester fetus lo ensure norma! brain development (Clandinin et id., I OS 1). Both albumin-bound fatty acids and fatty acids released from VLDI by LPI at the maternal face of the placenta arc available for transport. Fatty acid uptake is mediated by FATP. FABPpm, and fatty acid translocase (FAT), export to the fetal side involves mainly FATP (Dutta-Roy. 2000). The exact role and identity of these transporters remains to be clarified. The placental FABPpm, for instance, is not identical with the form in other tissues and transports essential fatty acids more effectively than smaller and saturated fatty acids. While long-chain essential fatty acids are preferentially transported across the placenta, the entire spectrum of fatty acids, including trans fatty acids, reaches the Tetus. Fatty acids in fetal circulation are bound largely to alpha-fetoprotein.

Metabolism

Oxidative metabolism: Fatty acids arc broken down through a diversity of pathways in at least three different organelle compartments. Beta-oxidation in mitochondria is the main fate of straight-chain fatty acids with 18 or fewer carbons. Peroxisomes lake care of the more unusual fatly acids, such as those with more than 18 carbons, At least two different alpha-oxidation pathways also operate in peroxisomes, one for phytanic acid and a different one for long-chain hydroxy acids, such as cerebrouic acid (2-hydroxy-tctracosanoic acid). Attack of the aeyl end of fatty acids in smooth endoplasmic reticulum produces dicarboxylic acids (omega-oxidation). With few exceptions the fatty acid metabolism begins with its conjugation to coenzyme A (CoA). Different ligascs act on the various fatty acids. Humans have at least six separate isoenzymes of long-chain-fatty-acid-CoA ligase (EC6.2.1.3) for the activation of fatty acids that differ in substrate preference and tissue expression pattern. The reaction is driven b\ ATP and subsequent pyrophosphate hydrolysis (inorganic pyrophosphatase: EC3.6.1J. magnesium-dependent).

Mitochondrial beta-oxidation: Muscle, heart and other tissues utilize fatty acids mainly via beta-oxidation in mitochondria. Carnitine is needed to shuttle medium- and long-chain fatty acids across the inner mitochondrial membrane. Long-chain fatty acid transport protein appears to participate in this transfer in an as yet unknown way. f irst, the fatty acid is activated by conjugation to CoA by one of several ligases differing in regard to preferred chain length. The resulting aeyl-CoA can permeate by diffusion

5-CoA

ubiquinol ubiquinone w ETF

c dehydrogenase { \ (FAD irun)

S-CoA

AcytCoA dehydrogenase

S-CoA

Trans- V-enoyl-acyt-CoA

Trans- V-enoyl-acyt-CoA

HO-CH

acetyl-CoA

acetyl-CoA

SH-CnA

HO-CH

L-3-Hydro*y-acyt-CoA

SH-CnA

3-hydioxy-acyl-CoA dehydrogenise.

NADH

3-hydioxy-acyl-CoA dehydrogenise.

NADH

3-Keto-aeyl-CoA

Figure 6.12 Mitochondrial beta-oxidation of fatty aodi across the porous outer mitochondrial membrane, on the inside of which il encounters palm itoy I -CoA: L-ca rn i t ine O-palmitoyl transferase 1. This enzyme transfers the fatty acid from CoA to carnitine and can then be taken across the inner mitochondrial membrane by a specific carrier (carniline-aeylcarnitine trans locase) ¡\ihtiiloy]-CoA:L-carnitine O-palmitoy I transferase II moves the fatty acid to CoA again, and exchange of the free carnitine for the next acylearnitine back across the inner membrane finally completes the cycle.

During each round of mitochondrial beta-oxidation the fatty acid is shortened by two carbons, reducing equivalents for oxidative phosphorylation are generated and one acetyl-CoA is released. These rounds proceed until lite final thiol ase cleavage generates either two acctvl-CoA (even-number chain length) or an acetyl-CoA and a propionyl-CoA (odd-number chain length). Depending on fatty acid chain length the initial step is catalyzed by long-chain acyl-C'oA dehydrogenase (EC 1.3.99.13. for CoA esters of straight fatty acids with 10 19 carbons), acyl-CoA dehydrogenase (ECl.3.99,3, for octanoyl-CoA). butvryl-Co.A dehydrogenase (ECI.3.99.2, for butyryl-CoA and hexa-noyl-CoA). 2-methyl-CoA dehydrogenase (EC1.3,99.12, for 2-mcthylbutanoyl-CoA and isobutyryl-CoA), and isovaleryl-CoA dehydrogenase (EC 1.3.99.10. for 3-methylhutanoyl CoA and valeryl-C'oA). All of these dehydrogenases contain FAD and use the I AD-containing electron-transferring llavoprotein (ETF) as acceptor. The clcctron-trdnsferripg-flavoprotein dehydrogenase (ECE5.5.I). which again contains FAD in addition to Us iron-sulfur centers, moves the electrons from reduced ETF to ubiquinol for utilization by oxidative phosphory lation. The subsequent enzymes for mitochondrial beta-oxidation arc 2-trans-enoyl-CoA hydratase (EC4.2.1.17). long-chain-3-hydroxyacyl-CoA dehydrogenase (EC 1.1.1.211), and acetyl-CoA C-aey I transferase (thiolase, EC2.3.U6). Segments with a double bond require the action of dodecenoyl-CoA delta-isomerase (EC5.3.3.8) instead of long-chain acyl-CoA dehydrogenase. C is-unsalurated fatty acids produce at some point a cis-delta2 aeyt-CoA intermediate. Dodecenoyl-CoA delta-isomerase (EC5.3.3.8) converts this cis-unsaturated compound into the normal trans isomer substrate of 2-trans-enoyl-CoA hydratase. and beta-oxidation can continue, if one or more double bonds follow, the acyl dehydrogenase reaction two cycles later generates eis-delta4-acyl-CoA. This intermediate is not a suitable substrate for 2-trans-enoyl-CoA hydratase, and requires instead the action of 2.4-dienoyl-CoA reductase (EC1.3.1.34) and then that of dodecenoyl-CoA delta-isomerase. These two reactions complete a round of beta-oxidation.

Mitochondrial beta-oxidation of branched fatty acids can lead to the generation of a 2-melhyl branched-acvl-CoA intermediate, which can then be oxidized by NAD-dependent 2-mcthyl-3-hydroxybutyryi-CoA dehydrogenase (M1IBD; ECU.1.178). This pathway parallels the breakdown of isoleucme. Acetyl-CoA acyl transferase (EC2.3.l.l6) cleaves the intermediate into propionyl-CoA and acetyl-CoA. Peroxisomal beta-oxidation of straight-chain fatty acids: The 'classical* peroxisomal betaoxidation pathway metabolizes saturated acyl-CoA with fatty acid carbons between 8 and 2b and no branching. Beta-oxidation becomes possible after linking to CoA. Fatty acids with twenty or more carbons are imported by the peroxisomal ABC halftransporter ALDP (*ALD* protein, defective in adrenoleukodystrophy) and estentied to CoA by very-long-chain acyl-C'oA synthetase (no EC number assigned). First, the acyl-CoA is oxidized to trans-2-enoyl acyl CoA by FAD-dcpendent acyl-CoA oxidase

(ECI.3.3.6), and then converted to L-3-hydroxyacyl Co A and 3-ketoacyl C'oA by peroxisomal multifunctional protein 2 <MFP2. comprising activities enoyl-CoA hydratase. K'4.2.1.17:3,2-trans-enoyl-CoA isomerase. EC5.3.3.8; and 3-hydroxyacyI-CoA dehydrogenase, ECI,1.1.35). Finally, acetyl-Co A and the shortened acyl-CoA are released by a pcroxisome-specific acetyl-CoA C-acyltransferase (3-ketoacyl-CoA thiolasc; EC2.3.1.16). Beta-oxidation usually tenninates in peroxisomes when a chain-length of 10 14 is reached and the resulting medium-chain acyl-C'oA is metabolized further in mitochondria.

Peroxisomal beta-oxidation of branched-cham fatty acids: An important example of branched-chain fatty acids is pristanic acid which results from alpha-oxidation of phytanic acid (Verhoevcn et a!., 1998). Branched-ehain fatty acids are activated by very-long-chain acyl-C'oA synthetase (EC unknown). either in the peroxisomes themselves or in mitochondria or endoplasmic reticulum. The branched-chain acyl-CoA is then oxidized by 2-methylacyl-CoA dehydrogenase (branched-chain acyl-CoA oxidase. ECI.3.99.12). metabolized to D-3-hydroxyacyl CoA and 3-ketoacyl CoA by

S-CoA

Long-chain acyl-CoA

Acyl-CoA oxidase ¡FAOt

S-CoA

ch3 ch

Acyl-CoA

CHj J1

Trans-A?-enoyl-acyl-CoA

acetyl-Ca A

Acyl-CoA

acetyl-Ca A

Figure 6.13 Peroxisomal beta-oxidation of fatly acidi

mfp2

L-3-Hydroxy-acylCoA

mfp2

L-3-Hydroxy-acylCoA

3-hydroxy-acyl CoA dehyarogenase

MADH

3-hydroxy-acyl CoA dehyarogenase

MADH

Figure 6.13 Peroxisomal beta-oxidation of fatly acidi peroxisomal multifunctional protein 2 (MFP2), and cleaved by the peroxisomal protein sterol carrier protein X (SCPx), which is not induced by dofihrate. Peroxisomal alpha-oxidation; Phytanic acid is metabolized in peroxisomes by phy-tanpyl-CoAdioxygenase (phytanoyl-CoA hydroxylase (EC1.14.1 LIU), cofactors iron and aseorbate). 2-Hydroxy-phytanoyl-CoA lyase (no EC number assigned, thiamin pyrophosphate and magnesium-dependent) then cleaves 2-hydroxy-phytanoyl-CoA into pristanal and tbrmyl-CoA t Foul on et at., 1999), After fatty aldehyde dehydrogenase (ALDH3A2; EC 1.2.1.3) has oxidized pristanal. the resulting pristanic acid undergoes further beta-oxidation in mitochondria.

The alpha-oxidation of cerebronic acid (2-hydroxytetracosanoic acid) from cerebro-sidesand sulfatides proceeds by a peroxisomal pathway distinct from that for phytanic acid (Sandhir 2000).

Microsomal omega-oxidation: Oxidation starting at the acyi end appears to contribute significantly to fatty acid metabolism in liver (Rognstad, 1995) and brain (Alexander ft al„ 1998). H proceeds only to a chain length of 12-14 carbons. The resulting dicar-boxylic acids are excreted with urine, Omega-2 oxidation, starting at the second carbon from the acyl end. also has been found to occur (Costa et al., 1996).

Omega oxidation may be of particular importance for the metabolism of cytotoxic products of fatty acid peroxidation. The typical product of laity acid peroxidation. 4-hydroxy-2-nonenal. can thus be oxidized to the less harmful 4-hydroxynonenoic acid (Laurent etui.. 2000).

NADP

NADPH

NADP

NADPH

NADPH-lernhemo-protein reductase (FMN. FAD)

NADPH-lernhemo-protein reductase (FMN. FAD)

NADP

reduced oxidized cytochrome cytochrome * O j H^O

reduced oxidized cytochrome cytochrome + Oj + HjO

COOH Oleic acta reduced oxidized cytochrome cytochrome * O j H^O

Cytochrome P450 (harne)

COOH

reduced oxidized cytochrome cytochrome + Oj + HjO

Cytochrome Piso (heme)

COOH

.COOH

Cytochrome P450 (harne)

Cytochrome Piso (heme)

COOH Oleic acta

COOH

10- Hydroxy-octadecerwc acid

COOH

IB-Carboxy-ociadecenotc acid

Figure 6.14 Microsomal omega-oxtdaiioit of Tally acids

Polyunsaturated fatty acids arc oxygenated by microsomal cytochrome P450-en/ymes in numerous additional ways ihat account for only a minute fraction of total metabolism, but may give rise 10 significant physiological and pathological effects. Fpoxidation, ally lie, and bis-allylic hydroxy lat i on, and hydroxy! ation with double bond migration have been described (Oliw, 1994),

Oxidized fatty acids: Stress, exertion, infection, and inflammation increase oxygen free radical generation and in consequence the exposure of unsaturated fatty acids to oxidative reactants. Double bonds in the aeyl moieties of phospholipids, cholesterol esters, and other complex fatty-acid-derived compounds are highly susceptible to oxidaiion upon free radical attack. Considerable amounts of oxidized fatty acids are also taken up when people consume fried foods (Staprans et ul., 1499; Wilson el ul.. 2002) and may lead to an inflated estimate of fatty acid peroxidation. A typical scenario is exposure of phospholipid acyl double bonds in the inner mitochondrial membrane to oxygen free radicals from oxidative phosphorylation reactions. Ensuing reactions may introduce a hydroxy] group adjacent to a trans double bond. Alternatively, a fatty aldehyde is generated. The main products of cholesteryllinoleaie from LDL exposed to monocytes are 9-hydroper-oxyoctadienoic acid and 13-hydropcroxyoctadienoic acid (Foleik and Cathcart, 1994).

The products of oxidized fatty acid metabolism, especially 4-hydroxy-2.3-trans-nonenal (UNE), crotonaldehyde. and inalondialdehyde, are highly reactive and cytotoxic metabolites that react with DM and proteins. Malondialdehyde is also a typical byproduct of prostaglandin synthesis from polyunsaturated faiiy acids. The reaction of malondialdehyde with DNA. identified by the formation of" pyrimido[ 1,2-a]purin-10(311 )-one and other adducts. greatly increases cancer risk (Mamett, 14W), Exposure of LDL to fatty aldehydes interferes with LDL-receptor-mediated clearance and increases lipid deposition in arteries (Tanaga et ul.. 2002), HNF can be conjugated to glutathione (by glutathione transferases A4-4 and 5.8: EC2.5. L18) and then pumped out of the cell by ATP-dependent transport that involves R.LIP76 (Cheng et ul.. 2001 >, Extracellular gamma-glutamyltranspeptidase (EC2.3.2.2) cleaves glutamate from the glutathione moiety and releases the cytotoxic conjugate cysteinvlglycine-4-hydroxy -2,3-trans-nonenal (Enoiu et a I., 2002).

HDL has a very high content of phospholipids with polyunsaturated fatty acids and is thus very susceptible to oxidative damage. Apolipoprotein A-l can terminate fatty acid radical chain reactions by directing the free radicals to core phospholipids and generate fatty aldehydes. Pantoxonase (PON, comprising activities of both arylesterase, EC3.1.1.2, and aryldialky I phosphatase. FC3,1.8.11 cleaves the fatty aldehydes from damaged phospholipids (Ahmed et ul.. 2001), The free fatty aldehydes can then be metabolized as outlined above. Two paraoxonases. PON) and PON3, are primarily associated with apolipoprotein A-l in HDL. The more ubiquitously expressed PON2 provides antioxidant protection for LDL and most tissues (NgtV a!.. 2001). The antioxidant potency of the paraoxonases appears to be distinct from the ability to cleave organophosphates. Paraoxonase activity shows as much as 40-fold \artaiion due to genetic polymorphism and dietary and exogenous factors including vitamin C and E status (Jarvik et at., 2002).

Acetyl-CoA oxidation. Mitochondria are the major site of acetyl-CoA utilization via the tricarboxylic acid (Krebs) cycle. Citrate synthase (EC4.1,3.7) joins acetyl-CoA to

Linoleyl phospholipid

Linoleyl radical

Ocia-9,H-dienyl radical

Octa-9.11-dienyl 13-peroxidyl radical

HO OH

Dihydroxyallylic radical

0c!a-9.n-dienyl 13-peroxidyl

E poxy ally lie radical

E poxy ally lie radical

""VWuA^AA/

Qcta-9,11 -dienyl 13-hydroxyI radical

4-Hydroxynonenal

AAAA-A^yW

13-Hydroxy octa-9.1 1-dienyl

-VVWWVW

Linoleyl phospholipid

-WWWVW'

Linoleyl radical

A/VWWWV"

Linoleyl phospholipid

AA/WWVW'

Linoleyl radical

Figure 6,15 Oxygen free radicals react with unsaturated Tatty acids

0_cvV\AAAAA

4-Hydroxynonenal* containing phospholipid

Paraoxonase (calcium)

a-Hydro*ynonenal

VWVNAAA

HO-CH-O —P—C—C—N—CH, I Hj Hj I OH * * CH;,

Lysophospholipid

Figura 6.16 Metabolism of oxidised fatty acids oxaloacetate. Tlic citrate from this reaction can then be metabolized further providing FADH, NADU, and succinate for oxidative phosphorylation and ATI1 or GTP from .succinyl-CoA.

Ketogenesis: The production rate ofacetyl-CoA from fatty acid beta-oxidation in the liver with prolonged fasting often exceeds the capacity of the krebs cycle. The coenzyme A for continued beta-oxidation and other functions can be released through the production of acetoacetate in three steps. Fnxymic reactions convert excess mitochondrial acetyl-CoA either to acetoacetate or 3-hydroxybutyrate (the main product): acetoacetatc can spontaneously decarboxylate to acetone. The term "ketone bodies' for all three products is misleading, but continues to be widely used. The acetyl-CoA condensation sequence frees up CoA for continued breakdown of fatty acids, mainly in the liver during extended periods of fasting or in situations of abnormally high lipolysis (as in diabetes due to low insulin concentration). Since the reactions occur in mitochondria, ketogenesis regulation is independent of the same reactions for cholesterol synthesis in cytosol. The typical odor of a fasting individual is partially related to exhaled acetone formed from acetoacetate. Tine conversion of acetoacetate into beta-hydroxybutyrate taxes the body's acid-butfering capacity and may cause a drop

Acetyl-Co A C-acety transferase

II II

Aceioaceiyi-CoA

HMG-CoA synthase

O OH

HMG-CoA synthase

HMG-CoA lyase

O II

hig-c—c—< N ^ HjC-C—c—c; -N ' • HjC-C-CH,

H OH 3-Hydroxyt>utyrate V0H nof,'enl^lc dehydrogenase

Figure 6.17 Metabolism of 'ketone bodies

¡l-hydroxybutyrate dehydrogenase Aceloacetale Acetone in blood pM (acidosis) in diabetics and similarly susceptible patients. None of these events is related to dietary intake of acetate in typical quantities.

Acetyl-CoA C-acety I transferase (thiolase. EC2.3.1.9) joins two acetyl-CoA molecules. and hydroxymethyIgl ute ry l-Co A synthase (HMG-CoA synthase: EC4.1.3.5) adds another one. The mitochondrial isoform of HMG-CoA synthase is genetically distinct from the cytosolic one, which generates the precursor for cholesterol synthesis.

1 lydroxymethylglutaryl-CoA lyase (HMG-CoA lyase. EC4.1.3.4) finally generates acctoacctatc by cleaving off acctyl-CoA from the I lMG-CoA intermediate. Spontaneous decarboxylation of acetoacetate generates the dead-end product acetone.

Aceloacetale can also be reduced to beta-hvdroxybuiy rate by NADM-dependcnt 3-hydroxybutyrate dehydrogenase (EC1.I.1.30). This enzyme is allosterically activated by phosphatidyl choline. 1 he reaction is fully reversible. Net flux depends on substrate

Proplonyi-CoA

Propionyi-CoA carboxylase (biotin, magnesium}

C-COOH

CoA-S-C

D -M ethylmalonyl-Co A

Meihyt-malonyi-CoA racemase

MethylmalonytCoA

muiase (adenosylcobalam in)

Malaie /

Fumatate \

Succinate

acetyl-Oxato- I CoA acetate

Citrate

Isocilraie

»-Ketogluiarate

Succinyl-CoA

Hjfure 6.18 The metabolism of propronyl-CoA from odd-ch.lin fatty at ids.

concentrations, Aeetoacetate and beta-hydroxybutyrate (hut not acetone) can become a significant energy fuel For brain alter several days of adaptation to starvation conditions, Propionyl-CoA metabolism: For continuation of its breakdown, propionyl-CoA has to be ferried from peroxisomes into mitochondria where the biotin-containing enzyme propionyl-CoA-carboxylase (EC6.4.1.3) adds a carbon. meihylmalonyl-CoA converts D-methylmalonyl-CoA into the I .-form, and mcthyImalony 1-Co A mutase (FX'5.4.99,2, contains 5'-deoxyadenosylcobalamin) finally produces the Krebs cycle metabolite succinyl-CoA.

Excretion

Normally neither free fatty acids nor fatty acid-conmining compounds are excreted via urine. Excretion with bile is minimal, mainly as a component of phospholipids that are readily reabsorbed from the small intestinal lumen. Thus, almost no fatty acid is lost from the body once it has been absorbed.

Storage

Fat is well suited for storage. It has by far the highest energy density of all nutrients and requires the smallest possible space, I'hc lack of electric charges and insolubility

HO-CH

The Most Important Guide On Dieting And Nutrition For 21st Century

The Most Important Guide On Dieting And Nutrition For 21st Century

A Hard Hitting, Powerhouse E-book That Is Guaranteed To Change The Way You Look At Your Health And Wellness... Forever. Everything You Know About Health And Wellness Is Going To Change, Discover How You Can Enjoy Great Health Without Going Through Extreme Workouts Or Horrendous Diets.

Get My Free Ebook


Post a comment