Stearoyl-coenzyme A desaturase (SCD) catalyzes the desaturation of saturated fatty acids to monounsaturated fatty acids in mammalian cells. Currently, there are four known enzymatic isoforms (SCD1-SCD4) in the mouse genome. The physiological roles for multiple SCD isoforms and their substrate specificities are unknown at present. We report here distinct substrate specificities for the mouse SCD isoforms. Each SCD isoform was able to complement the ole1 mutation in Saccharomyces cerevisiae through heterologous expression of transgenic SCD. Fatty acid analysis showed that mouse SCD1, SCD2, and SCD4 desaturate both C18:0 and C16:0, whereas mouse SCD3 uses C16:0 but not C18:0.We identify SCD3 as a mammalian palmitotyl-CoA D9-desaturase, and its existence in mouse helps explain distinct physiological roles for each SCD isoform. Supplementary key words stearoyl-CoA desaturase . oleate . palmitoleate . substrate specificity D9-desaturase is a fatty acid-modifying enzyme in the biosynthesis of monounsaturated fatty acids. Because this enzyme commonly introduces a cis double bond at the 9,10 position of stearoyl-CoA to form oleoyl-CoA, it has been commonly known as stearoyl-coenzyme A desaturase (SCD) (1-5). Four SCD isoforms (SCD1-SCD4) have been characterized in mice (6-9). All mouse SCD genes are colocalized to chromosome 19 (9).Despite the fact that the four SCD isoforms share .75% nucleotide and amino acid sequence identities, they differ in their 59-flanking promoter, which results in divergent tissue-specific expression (2). SCD1 is expressed in lipogenic tissues, including liver and adipose tissue (8). SCD2 is expressed primarily in the brain and neuronal tissue, particularly during the neonatal mylenation period (6). SCD3 expression is restricted to sebocytes in skin, preputial gland, and Harderian gland (9-11). SCD4 is expressed predominantly in heart (7). Mouse SCD1 and SCD2 are the best characterized isoforms because of the availability of SCD1 and SCD2 knockout mice (SCD1 2/2 and SCD2 2/2 ) (12, 13). Adult SCD1 2/2 mice exhibit a decrease in the synthesis of esterified lipids, including triglycerides, cholesteryl esters, and wax esters. As a consequence, SCD12/2 mice are protected against adiposity and liver steatosis, but they develop alopecia and close eye fissure (12,14,15). In contrast, SCD2 mice have a defect in skin permeability barrier formation and show a decrease in the synthesis of lipids during early development but not at late stages of development (13). These results have suggested that although SCD1 is crucial in adult mice, SCD2 controls lipid metabolism in early life.Currently, it is unknown why multiple SCD isoforms exist in mammalian genomes. Both the tissue-specific expression and the resulting phenotypes of SCD1 and SCD2 mouse isoform knockouts suggest that each isoform has a distinct physiological role; however, it is not clear how the enzymes accomplish the different roles biochemically. Liver microsomes from SCD1 2/2 and SCD2 2/2 mice displayed a decrease in the conversions of...
