20 II. BIOSYNTHESIS 



All of the above results, which illustrate the lipogenic activity of the 

 mammary glands, are uniform in indicating that milk fatty acids originate 

 largely in the udder itself, and that they are not merely excreted by this 

 organ after having been synthesized in the liver and carried to the mammary 

 gland in the blood stream. Moreover, the experimental data suggested 

 that the short-chain acids are not degradation products of oleic acid, as 

 postulated in the Hilditch theoiy, but rather arise by synthesis from 

 acetate. 



The conclusion is inescapable that acetate is an intermediate in the 

 synthesis of fat in the animal body. Moreover, not only the liver, but 

 many other extrahepatic tissues are able to bring about this synthesis of 

 fat. Mammary tissue has a particularly high capacity for fat production 

 from acetate, especially in the case of the ruminants. Although udders 

 of the non-ruminants lack the capacity to form fatty acids from acetate 

 in the absence of glucose, they do develop this facility when the mono- 

 saccharide is present. 



(3) The Mechanism of Synthesis of Fatty Acids from Acetate 



The synthesis of the fatty acids appears to be the result of successive 

 additions of two-carbon units to the carboxyl end of the fatty acids. Such a 

 condensation has been repeatedly demonstrated in the synthesis of the 

 C4 acids (especially acetoacetic acid), and considerable evidence for its 

 occurrence in longer chain acids is now available. 



a. The Synthesis of Acetoacetate from Two-Carbon Fragments. In 

 studying the origin of the acetoacetate from long-chain fatty acids, con- 

 siderable data have accumulated to indicate that the primary reaction in- 

 volves the formation of a two-carbon compound which is condensed to 

 yield the four-carbon ketone body acid, acetoacetic acid. 



The earliest proof that a condensation of two acetate molecules could take 

 place, with the resultant formation of acetoacetate, was that of Loeb,^^ 

 and also of Friedmann, ^^ who reported the formation of acetoacetate after 

 the liver had been perfused with acetate. This reaction has been confirmed 

 in liver slices by Jowett and Quastel,^" by Leloir and Munoz,^^ and by ■ 

 Weinhouse and co-workers in liver,*^ and in kidney slices,^^ with the la- 

 beled compound. Soodak and Lipmann'*'' demonstrated a synthesis of 

 acetoacetate when acetate, pigeon liver extract, and ATP were incubated. 



8» M. Jowett and J. H. Quastel, Biochem. J., 29, 2159-2180 (1935). 



81 L. F. Leloir and J. M. Munoz, Biochem. J., 33, 734-746 (1939). 



82 S. Weinhouse, G. Medes, and N. F. Floyd, J. Biol. Chem., 153, 698-690 (1944). 



83 G. Medes, S. Weinhouse, and N. F. Floyd, J. Biol. Chem., 157, 751-752 (1945). 



