Problems in Lipide Metabolism 135 



It is not surprising thai a number of questions are raised by these 

 striking discoveries. One of these concerns itself with the manner in 

 which the fatty acid moieties of phospholipidcs, triglycerides, and 

 other naturally occurring esters are converted into activated fatty 

 acids. In this connection, a very promising start has been made by 

 Kornberg and Pricer who have demonstrated that acyl CoA derivatives 

 can be enzymatically esterified with L-a-glycerophosphate to yield 

 phosphatide acids. If this type of reaction should prove to be revers- 

 ible (and thermodynamically this seems likely), a thiolytic cleavage 

 would be clearly involved as the initiating step rather than a reaction 

 involving the hydrolytic action of lipase. The detailed mechanism 

 of the initial activation clearly needs further investigation. 



Although the reversibility of all of the chemical steps of the oxidative 

 cycle seems likely, it has been difficult to establish this experimentally. 

 Stansly and Beinert J1 have been able to demonstrate with purified 

 enzymes the conversion of labeled acetyl CoA to butyryl CoA, pro- 

 vided suitable hydrogen donors were present. Since the thiolytic 

 cleavage of /?-ketoacyl CoA proceeds nearly to completion, 8 ' 12 some 

 driving force is necessary to shift the equilibrium in favor of synthesis. 

 Esterification may be an important reaction for this purpose even 

 though this obviously does not provide a complete answer to the 

 problem of lipogenesis. 



Before turning to problems of lipogenesis, a brief comment should 

 be made about another aspect of the oxidation problem. The original 

 reports 13 that two types of metabolically different 2-carbon fragments 

 are produced during the oxidation of fatty acids have been amply 

 confirmed. According to this concept, the bulk of the 2-carbon frag- 

 ments are probably acetyl CoA (originally described as — CH;.— CO— 

 groups). The terminal two carbons of the fatty acid being oxidized 

 give rise to a fragment (originally described as CH 3 — CO— ) which 

 preferentially contributes to carbons 3 and 4 of acetoacetate. In other 

 words, not all of the 2-carbon fragments derived from fatty acids 

 are symmetrically incorporated into the two halves of acetoacetate. 

 Lynen 14 has invoked the concept of an acetyl-enzyme complex to 

 describe the behavior of the terminal fragment, whereas Beinert and 

 Stansly 15 picture it as an acetyl-CoA-enzyme complex. 



CH 3 CO*-enzyme (CH 3 CO— CoA-enzyme) + CH 3 CO— CoA ^ 



CH 3 CO*CH 2 CO— CoA + Enzyme 



Asymmetrically labeled acetoacetate would in either case be formed. 

 Although these theories are not easy to prove, they are attractive and 



