Fluoromorphic Substrates for Fatty Acid Metabolism: Highly Sensitive Probes for Mammalian Medium-Chain Acyl-CoA Dehydrogenase

✍ Scribed by Mary K. Froemming; Dalibor Sames

• Book ID: 101536564
• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 203 KB
• Volume: 118
• Category: Article
• ISSN: 0044-8249
• DOI: 10.1002/ange.200502675

✦ Synopsis

In contrast to the accepted view in biological sciences that enzymes are highly selective for their physiological substrates, substrate promiscuity is a widespread phenomenon. [1] Such functional flexibility may often be observed with enzymes involved in the metabolism of an array of substrates, and examples extend beyond the well-known xenobiotic metabolism.

The exploration of enzyme substrate flexibility for the purpose of the development of metabolic probes and imaging agents represents a guiding concept for a broad program in our laboratories. [2,3] Herein we report the examination of the substrate fidelity of medium-chain acyl-CoA dehydrogenase (MCAD), a key enzyme in the metabolism of fatty acids, which led to the development of fluorogenic and fluoromorphic probes for this enzyme. [4] These indicators allow for selective and sensitive detection of MCAD activity in tissue homogenate.

b-Oxidation of fatty acids represents one of the central metabolic pathways. [5][6][7][8][9][10][11] Close examination of this process reveals considerable built-in substrate flexibility. Catabolism of a long-chain fatty acid occurs by repetitive removal of twocarbon units (acetyl-CoA), (Figure 1). Each catalytic turn involves four chemical steps that are catalyzed by enzymes capable of accommodating substrates with a variety of chain lengths. Thus, instead of having a specific enzyme for each intermediate (C 16 , C 14 , C 12 !C 2 ), this pathway consists of a few enzymes that show broad and overlapping chain-length specificities.

The overall mechanism for this pathway was proposed on the basis of classical studies conducted by F. Knoop [12] who showed that w-phenyl fatty acids were metabolized in dogs.