The Catabolism Of Acylglycerols

This section is concerned entirely with the hydrolysis of fatty acids from one or more positions on the glycerol backbone of acylglycerols, catalysed by enzymes termed lipases, which act mainly at the surfaces of large fat particles.

Catabolism refers to the metabolic breakdown of complex biological molecules. One of the main themes running through this book is that, with very few exceptions, lipids in biological tissues are in a dynamic state: they are continually being synthesized and broken down. This is known as turnover. Complete catabolism of acylglycerols takes place in two stages. Hydrolysis of the ester bonds that link fatty acyl chains to the glycerol backbone is brought about by enzymes known as lipases. Following the action of a lipase, releasing fatty acids, these may be further catabolized by oxidation (Section 2.3). Acylglycerols themselves are not substrates for oxidation. Alternatively, however, the fatty acids released from acylglycerols may follow other metabolic pathways, including re-esterification with glycerol to make new acylglycerols. Therefore the lipases may be seen as 'gatekeepers', releasing fatty acids from the acylglycerol energy stores for oxidation or for further metabolism.

There is a large number of lipases, some related in families, and they differ in respect to their substrates and the positions in substrates of the bonds that they hydrolyse. There are also many enzymes called esterases that hydrolyse ester bonds in general, but lipases form a distinct class and the distinction lies in the physical state of their substrates. The milieu in which a lipase acts is heterogeneous: the lipid substrate is dispersed as an emulsion in the aqueous medium, or is present as a fat droplet (e.g. within the mammalian adipocyte), and the enzyme acts at the interface between the lipid and aqueous phases. If, by some means, a single-phase system is obtained, for example when the tria-cylglycerol contains short-chain fatty acids (as in triacetin) or when a powerful detergent is present, then the lipid may be hydrolysed by an esterase, not a lipase.

Our understanding of lipase action has increased markedly in recent years with the use of X-ray crystallography to determine the three-dimensional structure of one such enzyme, pancreatic lipase (Section 5.1.1). This work, which has involved the crystallization of pancreatic lipase in the presence of emulsified fat, has provided a mechanistic basis for the phenomenon of interfacial activation, the activation of the enzyme that occurs on the surface of an oil-in-water droplet. Most importantly, in the presence of emulsified lipid, conformational changes in the enzyme lead to the opening of a 'lid' that allows access of the substrate to the active site. This lid-opening mechanism appears to be common to other members of the same family of lipases.

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