Hco Wwwv

vWSAAAA

1 -palmilyl-2-patmity!-sn-glycerol (a mixed diglyceride)

IAAAAAAA

IAAAAAAA

1 -paimilyl-2-palmityl-3-bulyryl-sn-glycerol (a mixed triglyceride)

CH-0

^AA/UAAM

0 CH3 11 I

OH CH3

1 - pa! m ityl-2-oleyl-phosphatidyl choline (a phospholipid)

CH-O

AAAA=AAAA

o II

I Hj Ha OH

1 -pa I mily I-2-oieyi-phosphatidyl-ethanolamine (a phospholipid)

Figur* 6.7 Fatty acids arc part of different complex lipid»

Cholesterol

typically derived from bacterial sources, while some of the longer ones are produced in mammals (including man) by extension of valine metabolites (¡so-fatty acids) and isoleucine metabolites (anteiso-faiiy acids). Recent evidence also points to a specific role of branched long-chain fatty acids (including 18-meihylcicosanic acid), some of them hydroxyfated and/or with double bonds, as structural components of hair (Jones and Riven, 1997). skin and fatty secretions (sebum) from skin (Steward and Downing, 1990). Phytanic acid and pristaiiie acid are mostly derived from phytol, which provides the side chain of chlorophyll and has multiple methyl branches.

The bulk of dietary fatty acids is bonded to glycerol. Monoglycerides contain one fatty acid, diglycerides contain two. and triglycerides contain three, A large percentage of cholesterol and plant sterols in foods is esterified to a fatty acid more likely an unsaturated than another kind of fatty acid. Phospholipids by definition contain fatty acids.

The appearance of dietary fats (triglycerides) provides clues about their fatty acid composition. Fats that are solid (white) at room temperature are composed mainly of saturated fats. Oils, which are triglycerides that are liquid at room temperature, contain significant percentages of unsaturated fats.

Endogenous sources

Complete de novo synthesis The extent to which carbohydrates are converted into fat is still under dispute (Hellerstein, 2001). So much seems certain: The liver produces only a few grams of fat per day from acetyl-CoA even during periods of massive carbohydrate overfeeding. Adipose tissue may be responsible for conversion of carbohydrate into fat at a much higher rate (Aarsland t•ml.. 1997). Synthesis, as far as it takes place, tends to proceed to chain lengths of 16 or 18 carbons with little release of the intermediate metabolite myristate.

Synthesis depends on plentiful supplies of acetyl-CoA, w hich is moved from mitochondria to the cytosol by the citrate shuttle mechanism. C itrate, which is produced from acetyl-CoA and oxaloacetic by citrate synthase (EC'4.1.3.7), moves across the inner mitochondrial membrane via the tricarboxylic transporter (SLC25A1) in exchange for malate. ATP-citrate (pro-S-)-lyase (citrate cleavage enzyme: EC4.1.3.8) can then release acetyl-CoA for fatty acid synthesis and malate for transport back into mitochondria and another cycle of aeetyl-C'oA export. Alternatively. NADP-dependent malic enzyme I (EC 1.1 1.40) can generate pyruvate, which in turn is shuttled back into mitochondria.

The first key step of fatty acid synthesis and elongation in cytoplasm a is malonyl-CoA production by acetyl-CoA carboxylase (EC6.4.1.2). I his enzyme is biotinvlated by biolin-[acetyl-CoA-carboxylasc| ligase (EC6.3.4.15), inactivated by [acetyl-CoA carboxylase] kinase (EC2.7.I.128). and reactivated by [acetyl-CoA carboxylase]-phosphatase (EC3,1.3.44). Two genes encode isoenzymes with different tissue expression patterns. The alpha enzyme is expressed in muscle and many oiher tissues except liver. The beta enzyme in muscle and liver occurs in short and long isoforms due to alternative splicing.

Fatty acid synthase (EC2.3.1.85) is a multi-enzyme complex in the acyl-carrier protein which moves the growing fatty acyl-CoA chain from site to site until the full-length chain is released. A notable feature of acyl-carrier protein is the phosphopantctheine group. Holo-acy I-carrier protein synthase (EC2.7.8.7) transfers this Co A-de rived molecule to a specific serine group of the nascent protein, Acyl-carrier protein is the only use of pantothenate in a form other than coenzyme A.

o ll

Malonyi-CoA ACP

ACP Smalonyl N^ transferase

NADP

NADPH

ACP Smalonyl N^ transferase

NADP

NADPH

NADPH

NADP

(i -hydroxyacyl

Figure 6.8 Df now synthesis is usually a minor source of fatty acids in humans

NADPH

NADP

(i -hydroxyacyl

Figure 6.8 Df now synthesis is usually a minor source of fatty acids in humans

The fatty acid synthase complex comprises components that catalyze the reactions of acyl-carrier protein S-acetvl transferase (EC2.3.1.38), acy¡-carrier protein S-mal-onyltransferase (EC2.3.1.19), 3-oxoaeyl-acyI-carrier protein synthase (EC2.3.1.41i. 3-oxoacyl-acyl-carrier protein reductase (EC LI. I. MX)), 3-hydroxypalmitoyl-acyl-carrier protein dehydratase (EC4.2. 1.61), enoy I-acyl-carrier protein reductase (NADPI I. B-specilic) {EC1.3.LI0), and oleoyI-acyl-carrier protein hydrolase (EC3.1.2.I4).

HOOC

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