300 



F. LYNEN, S. OCHOA 



VOL. 12 (1953) 



that the active intermediates might be the CoA derivatives of the fatty acids^'-^'^". This 

 behef was reinforced by the observation that S-acetyl CoA or the S-acyl derivatives of 

 higher fatty acids can be generated enzymically through a reaction ot the fatty acid with 

 acyl phosphates in the presence of CoA^^-eo or with CoA and ATPii'44'i5,36,49,72,23,i6,4i,6-_ 



Finally, work on the enzymic breakdown and synthesis of acetoacetate and other /3-keto 

 fatty acids'^' '^'''^'^^''^'^'"*'^^'^' 2^ '^^'2- opened the way for an understanding of the 

 mechanism whereby fatty acid chains are shortened or elongated, by the removal or 

 addition of acetyl CoA, during fatty acid oxidation or synthesis. 



By employing synthetic S-acyl analogues of the fatty acid derivatives of CoA"*^- ^^ 

 or the CoA fatty acid derivatives themselves^- ^^'^^ more recently made available by 

 chemical or enzymatic synthesis, it has been possible to characterize and isolate from 

 animal tissues some of the enzymes of fatty acid metabolism and obtain a clearer picture 

 of the process as a whole. The development of rapid and sensitive optical methods of 

 assay, whose introduction in enzymology we owe to Otto Warburg, has greatly 

 facilitated the task of purifying the individual enzymes and studying their mechanism of 

 action. The work described in this paper owes much to Warburg's pioneering contri- 

 butions which opened up new avenues of approach to dynamic biochemistry. 



Fatty acid cycle 



The results of the work summarized above and of the more recent work to be 

 discussed in this paper show that fatty acid oxidation and synthesis proceed through 

 the reactions illustrated in Fig. i. 



Fatty acid synthesis is accomplished through repetition of a cycle of four con- 

 secutive reactions: (a) condensa- 

 tion of two molecules of acetyl 

 CoA to form acetoacetyl CoA and 

 CoA-SH, (b) reduction of aceto- 

 acetyl CoA to j8-hydroxybutyryl 

 CoA, (c) dehydration of /3'-hy- 

 droxybutyryl CoA to crotonyl 

 CoA, and (d) reduction of crotonyl 

 CoA to butyryl CoA. A new cycle 

 is started by the reaction of 

 butyryl CoA with another mole- 

 cule of acetyl CoA, to form ^-keto- 

 caproyl CoA+CoA-SH, and so 

 forth. The cycle is repeated eight 

 times until stearyl CoA is formed. 

 All four reactions of the fatty acid 

 cycle are reversible and fatty acid 

 oxidation, once the fatty acid is 

 activated through conversion to the corresponding acyl CoA derivative, proceeds by a 

 reversal of the above sequence. The acetyl CoA split off at the end of each sequence is 

 either oxidized via the citric acid cycle, by reacting with oxalacetate to form citrate and 

 CoA-SH^i'''\ or is converted to acetoacetyl CoA -fCoA-SH. In liver, acetoacetyl CoA 

 is hydrolysed by a specific deacylase with formation of CoA-SH and acetoacetate*"'^^'^'*''^. 

 The presence of this enzyme would seem to account for the formation of free aceto- 

 Refercnces p. 313J314. 



FATTY ACID CYCLE 



(FAOHjsaFAD) 

 -2H 



-CHj-CHj-CHg-CO 



CHj-CH'CH-CO-S-CoA 



HS-CoA 



CHg-CH-CHj-CO-S-CoA 



-2H 



(DPN*wSOPNH tH*) 



Fig. I. Fatt}- acid cycle 



