\()L. 12 (1953) BIOCHIMICA ET BIOPHYSICA ACTA 299 



ENZYMES OF FATTY ACID METABOLISM* 



by 



FEODOR LYNEN 



Biochemische Abteilung, Chemisches Universitdts-Lahoratorium, Munchen {Deutschland) 



AND 



SEVERO OCHOA 

 Department of Pharmacology, New York Universitv College of Medicine, New York, N .Y. {U.S.A.) 



Work of recent years (for reviews see ^' ^' ^^) has thrown much hght on the mechanism 

 of the j8-oxidation of fatty acids formulated by Knoop in 1904^-. Through the use of 

 isotopic tracer techniques'"*' ^^''^^ and of cell-free tissue preparations capable of oxidizing 

 fatty acids^"' ■*^' ^''~^''' 2'*' ^^' ^^ it was established that the two-carbon units removed 

 successively from fatty acid chains during /3-oxidation are identical to the two-carbon 

 units derived from carbohydrate through the oxidative decarboxylation of pyruvic 

 acid^^. Further, these units can either condense with one another — -or with longer fatty 

 acid chains — -to bring about fatty acid synthesis, or can undergo oxidation via the 

 citric acid cycle''*' ^^'^'^^'^'''^*'. Work with extracts of Clostridium kluyveri demonstrated 

 that fatty acid synthesis occurs by a reversal of j8-oxidation^^~^^' ^^. Evidence was also 

 obtained that in the process of synthesis, in both bacteria'*' ^^ and animal tissues^- '^'^2, 

 the methyl end of "acetic acid" units is added to the carboxyl end of a fatty acid chain. 



Further progress was hampered by the failure to detect intermediates during fatty 



acid oxidation or synthesis although from the early work of Dakin^^ the corresponding 



a,/3-unsaturated, j8-hydroxy- and /S-keto derivatives would be expected to be involved. 



Such a view would be in agreement with the observations that, at least in some tissues, 



the above compounds are oxidized at about the same rate as the corresponding tatty 

 acids3i.2o. 



The finding that fatty acids are not oxidized unless they undergo a preliminary 

 activation and the fact that this activation is dependent on the generation of energy-rich 

 phosphate^'''*^'3''3^'*2'2*''3^'^*'®2,63,29,i5,i6 suggested that the actual intermediates might 



not occur as the free acids'^. The identification of the two-carbon unit as S-acetyl co- 

 enzyme A**^^'^''^^'^*'''^'^*'^^'^^ shed new light on the problem and strongly suggested 



* The experimental work reported in this paper was aided by grants from the Deutsche For- 

 schungsgemeinschaft and the Firma C. H. Boehringer Sohn, Ingelheim (University of Munich), and 

 the United States PubUc Health Service, the American Cancer Society (recommended by theCommitee 

 on Growth of the National Research Council), and by a contract (N6onr2 79, T.O. 6) between the 

 Office of Naval Research and New York University College of Medicine. The authors are indebted to 

 the Rockefeller Foundation for travelling fellowships which facilitated collaboration between their 

 two laboratories. 



** The following abbreviations are used '.Coenzyme A (reduced), CoA, CoA-SH or CoA-SH; S-acyl 

 coenzyme A derivatives, S-Acyl CoA, acyl-S-CoA, acyl-S-CoA, or simply acyl CoA; adenosine tri- 

 phosphate, ATP; adenosine-5'-phosphate, AMP; pyrophosphate, PP; oxidized and reduced di- 

 phosphorpyridine nucleotide, DPN+ and DPNH; oxidized and reduced flavin adenine dinucleotide, 

 FAD and FADHg. 



References p. 313J314. 

 19 



