Lecture 22 Summary

Regulation of acetyl CoA carboxylase

Most of the regulation of fatty acid synthesis occurs at the committed step, that is the step catalyzed by acetyl CoA carboxylase. As we have seen for glycogen synthase, regulation of this enzyme occurs by allosteric mechanisms and phosphorylation/dephosphorylation. The former is responsive to metabolic conditions, while the latter is coordinated by physiological factors that dictate the hormonal balance of the organism.

Elongation and desaturation in fatty acid synthesis

Since fatty acid synthase produces only a saturated, C16 product (palmitate), longer chain fatty acids and those containing double bonds (unsaturated fatty acids) must be produced by separate elongation and desaturation reactions. In eukaryotic cells the corresponding enzymatic activities are associated with the endoplasmic reticulum (ER). There are limitations on what can be produced in mammals. Linolenate is an w-3 fatty acid that mammals lack the capacity to produce. It is therefore referred to as an essential fatty acid. The number of carbons, and double bonds, as well as their locations and configurations, is specified for linolenate by the notation 18:3 cis-D9, D12, D15.

Arachidonate and eicosanoid signaling molecules

Arachidonate is derived from the essential fatty acid linoleate. Linoleic acid is an w-6 fatty acid, and the dietary requirement for w-6 fatty acids is at least in part due to its conversion to arachidonate, which is itself a precursor of several important classes of signaling molecules. These molecules, collectively referred to as eicosanoids (autacoids), are involved in a large variety of physiological processes, such as inflammation and other aspects of immune system response, regulation of blood flow and clotting, ion transport, synaptic transmission, and reproductive phenomena. The major classes of eicosanoids are the prostaglandins, prostacyclins, thromboxanes, and leukotrienes.

Much of the arachidonate that is destined to become eicosanoid molecules is converted to the common precursor of prostaglandins, prostacyclins, and thromboxanes by prostaglandin-endoperoxide synthase [EC 1.14.99.1] - also sometimes referred to as PGH₂ synthase or prostaglandin synthase, but quite commonly referred to simply as cyclooxygenase (COX). The synthase has two distinct activities - a cyclooxygenase activity that utilizes molecular oxygen to attach peroxide to arachidonate, while at the same time introducing a cyclopentane ring. This intermediate product is referred to as PGG₂. A subsequent reductive step - the peroxidase step - takes place at distinct site within the enzyme, and forms the product PGH₂. This is itself quite labile, and is normally converted into one of many eicosanoid derivatives, depending on the context. Isomerases convert PGH₂ into the different types of prostaglandins. Prostacyclin synthase converts PGH₂ into PGI₂, which undergoes further conversions. Thromboxane synthase converts PGH₂ into TXA₂, which can also undergo further conversion (see figure below).

An interesting pharmacological feature of COX enzymes is that they are inactivated by aspirin (acetylsalicylate). The inactivation is due to aspirin's ability to acetylate a serine residue of COX that is necessary for catalysis. Although aspirin itself was one of the first drugs ever synthesized, and herbal remedies based on plants containing salicylate derivatives have been used for centuries, the mode by which aspirin exerts its effects was not understood until 1971, when John Vane discovered that aspirin blocked the formation of prostaglandins and thromboxanes. The therapeutic utility of aspirin is now thought to be largely due to this effect, as these eicosanoids have an impressive range of physiological effects. Sune Bergström, Bengt Samuelson, and Vane were awarded the 1982 Nobel Prize in Physiology or Medicine for their discoveries concerning "prostaglandins and related biologically active substances".

Aspirin is a member of a broad class of drugs called non-steroidal anti-inflammatory drugs, or NSAIDs. Also in the class are ibuprofen and naproxen.

Study questions

• Describe the regulation of ACC.
• Explain why arachidonate is an important unsaturated fatty acid.
• Discuss the reasons why aspirin is antiinflammatory, antipyretic, an analgesic, and taken to reduce chances of thrombosis.

Page updated 12-27-06

References

1. Berg, Tymoczko, and Stryer. Biochemistry (BTS): 6th edition (2007, Freeman) Ch.22, pp.640-646; Ch.27, pp.760-775. See also p.338-339.