Учебное пособие: Lipid biosynthesis

gradient: either a citrate/phosphate antiport or a citrate/malate antiport as shown in Figure 2-2.

Fatty acid biosynthesis (and most biosynthetic reactions) requires NADPH to supply the reducing equivalents. Oxaloacetate is used to generate NADPH for biosynthesis in a two-step sequence.

The first step is the malate dehydrogenase reaction found in the TCA cycle. This reaction results in the formation of NAD from NADH (the NADH primarily comes from glycolysis). The malate formed is a substrate for the malic enzyme reaction, which makes pyruvate, CO2, and NADPH. Pyruvate is transported into the mitochondria where pyruvate carboxylase uses ATP energy to regenerate oxaloacetate.

Palmitate is the starting point for other fatty acids that use a set of related reactions to generate the modified chains and head groups of the lipid classes. Microsomal enzymes primarily catalyze thesechain modifications. Desaturation uses O2 as the ultimate electron acceptor to introduce double bonds at the nine, six, and five positions of an acyl-CoA.

Elongation is similar to synthesis of palmitate because it uses malonyl-CoA as an intermediate. See Figure 2-3.

Synthesis of Triacylglycerols

Glycerol accepts fatty acids from acyl-CoAs to synthesize glycerol lipids. Glycerol phosphate comes from glycolysis-specifically from the reduction of dihydroxyacetone phosphate using NADH as a cofactor. Then the glycerol phosphate accepts two fatty acids fromfatty acyl-CoA. The fatty acyl-CoA is formed by the expenditure of two high-energy phosphate bonds from ATP.

Cholesterol Biosynthesis and its Control

Despite a lot of bad press, cholesterol remains an essential and important biomolecule in animals. As much as half of the membrane lipid in a cellular membrane is cholesterol, where it helps maintain constant fluidity and electrical properties. Cholesterol is especiallyprominent in membranes of the nervous system.

Cholesterol also serves as a precursor to other important molecules. Bile acids aid in lipid absorption during digestion. Steroid hormones all derive from cholesterol, including the adrenal hormones that maintain fluid balance; Vitamin D, which is an important regulatorof calcium status; and the male and female sex hormones.

Although humans wouldn’t survive in one sense or another without cholesterol metabolites, cholesterol brings with it some well-known side effects. Doctors find cholesterol derivatives, being essentially insoluble in water, in the deposits (plaque) that characterize diseased arteries.

HMG CoA Reductase

HMG-CoA reductase is the committed and therefore the regulatory step in cholesterol biosynthesis. If HMG-CoA is reduced to mevalonate, cholesterol is the only product that can result. The reduction is a two-step reaction, which releases the Coenzyme A cofactor and converts the thiol-bound carboxylic group of HMG-CoA to a free alcohol. Two NADPH molecules supply the reducing equivalents because the thioester must first be reduced to the level of an aldehyde and then to an alcohol.

Mevalonate Squalene

Mevalonate molecules are condensed to a 30-carbon compound, squalene. The alcohol groups of mevalonate are first phosphorylated. Then they multiply phosphorylated mevalonate decarboxylates to make the two compounds isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP).

mevalonate ® phosphomevalonate ® pyrophosphomevalonate

First, the other hydroxyl group of mevalonate accepts a phosphate from ATP. The resulting compound rearranges in an enzyme-catalyzed reaction, eliminating both CO2 and phosphate. The5-carbon compound that results, IPP, is rapidly isomerized with DMAPP.

In plants and fungi, IPP and DMAPP are the precursors to many so-called isoprenoid compounds, including natural rubber. In animals, they are mainly precursors to sterols, such as cholesterol. The first step is condensation of one of each to geranyl pyrophosphate,which then condenses with another molecule of IPP to make farnesyl pyrophosphate. Some important membrane-bound proteins have a farnesyl group added on to them; however, the primary fate of farnesyl pyrophosphate is to accept a pair of electrons from NADPH and condense with another molecule of itself to release both pyrophosphate groups.

The resulting 30-carbon compound is squalene; it folds into a structure that closely resembles the structure of the steroid rings, although the rings are not closed yet.

Squalene ® Lanosterol

The first recognizable steroid ring system is lanosterol; it is formed first by the epoxidation of the double bond of squalene that was originally derived from a DMAPP through farnesyl pyrophosphate, and then by the cyclization of squalene epoxide. The enzyme that forms the epoxide uses NADPH to reduce molecular oxygen to make the epoxide.

Lanosterol ® Cholesterol

This sequence of reactions is incompletely understood but involves numerous oxidations of carbon groups, for example, the conversion of methyl groups to carboxylic acids, followed bydecarboxylation. The end product, cholesterol, is the precursor to cholesterol esters in the liver and is transported to the peripheral tissues where it is a precursor to membranes (all cells), bile salts (liver), steroid hormones (adrenals and reproductive tissues), and vitamin D (skin, then liver, and finally kidney).

Cholesterol Transport, Uptake, and ControlCholesterol is expor ted to the peripheral tissues in LDL and VLDL (see Chapter 1). About 70 percent of the cholesterol molecules in LDL are esterified with a fatty acid (for example, palmitate) on the OH group (at Carbon 3; see Figure 2-5). Cells take up cholesterol from the LDL by means of LDL receptors in the outer cell membrane.