HANDBOOK OF PHYSIOLOGY -^ CIRCULATION I 



without a net oxidation of amino acid. Glutamate 

 can be oxidized directly by glutamic dehydrogenase 

 present in mitochondria, but the equililjrium constant 

 favors glutamate formation (173)- 



FATTY ACID OXIDATION. Fatty acids and their partial 

 oxidation products /i-hydroxybutyric acid and aceto- 

 acctic acid are rapidly oxidized by cardiac muscle 

 and, under conditions of fasting, may contribute as 

 much as 80 per cent of the energy required by the 

 heart. The j3-oxidation hypothesis of Knoop (124), 

 developed by feeding intact animals phenyl-fatty 

 acids, has been elaborated in an elegant manner at 

 the enzymatic level by Lehninger (132), Lynen (144), 

 and Green (87) during the past two decades. 



The sarcosome is the seat of the enzymes concerned 

 with fatty acid oxidation. Fatty acids presented to 

 the heart via nonesterified fatty acids bound to al- 

 bumin (NEFA) are transported to the mitochondrion 

 probably via the endoplasmic reticulum. An obliga- 

 tory reaction for further oxidation is the conversion 

 of these fatty acids to ac)l-S-CoA derivatives by the 

 following reaction: 



fatty acid -f- Co.-^— SH + ATP 



thiokinase 



Mg^ (9) 



acyl— S— Co.\ -f .\MP -|- PP 



Three distinct thiokinases are known which carry 

 out this reaction for fatty acids of different chain 

 length, one for acetic and propionic acids discussed 

 previously, one for acids of chain length C4-12 (146), 

 and one for acids of chain length C10-18 (126). The 

 /3-oxidation of the CoA derivative then proceeds to 

 produce two-carbon units sequentially as molecules 

 of acetyl-coenzyme A which may undergo any of the 

 possible fates of acetyl-CoA. In heart muscle, all but 

 a very small percentage is oxidized to CO2 and H2O 

 via the citric acid cycle. 



More specifically, fatty acyl-CoA derivatives are 

 oxidized in three steps to the corresponding /3-ketoacyl 

 derivative and then subjected to fission by the enzyme 

 i3-ketoacyl-CoA thiolase in the presence of CoA — SH 

 to form a molecule of fatty acyl-CoA derivative two 

 carbons shorter in length than the original, plus a 

 molecule of acetyl coenzyme A. This process is re- 

 peated until the fatty acid is completely degraded to 

 acetvl-CoA, v iz. : 



R— CH,— CH2— CO— S— Co.\ + FAD 



fatty acyl CoA dehydrogenase 



R— CH=CH— CO— S— CoA + FADH, 



R— CH=CH— CO— S— CoA + HOH 



unsaturated fatty acyl — CoA hydrase ( , , ) 



RCHOH— CHj— CO— S— CoA 

 RCHOH— CH2— CO— S— CoA + DPN+ 



(3-hydroxyacyl — CoA dehydrogenase (,2) 



R— CO— CHo— CO— S— CcA + DPNH + H+ 

 RCO— CHo— CO— S— CoA -|- CoA— SH 



0-ketoacyl — CoA thiolase (j„) 



RCO— .S— CoA -t- CH3— CO— S— CoA 



The initial oxidation of the fatty acyl-CoA deriva- 

 tive is FAD-dependent and hence electrons from this 

 oxidation enter the electron transport chain at a 

 different point than do those from the DPX catalyzed- 

 oxidation of the (3-hydroxylacyl-CoA derivative. 

 Twenty-five per cent of the energy of a fatty acid is 

 released during the first two oxidative steps leading 

 to acetyl-CoA formation and 75 per cent is released 

 during the subsequent reactions of the citric acid 

 cycle. 



The ketone bodies, acetoacetate and d( — ) /3-hy- 

 droxybutyrate, produced in li\'er as by-products of 

 fatty acid metabolism through the action of aceto- 

 acetyl-CoA deacylase and /3-hydroxybutyric acid 

 dehydrogenase, are well oxidized by the intact heart 

 and by heart sarcosomes. /3-Hydro.\ybutyric acid is 

 oxidized to acetoacetate by a DPN-dependent de- 

 hydrogenase present in sarcosomes. The acetoacetate 

 is then activated by an acyl transferase enzyme driven 

 by the energy-rich succinyl-CoA (225) as follows: 



succinyl — CoA -\- acetoacetate 



— • acctoacetyl — CoA -|- succinate 



(14) 



(■0) 



The acetoacetyl-CoA then undergoes cleavage by 

 /3-ketoacyl-CoA thiolase to form 2 moles of acetyl- 

 CoA which then undergoes terminal oxidation in the 

 citric acid cycle. No acetoacetyl-CoA deacylase is 

 present in heart muscle so that no loss of acetoacetate 

 can occur. 



Energy Conservation 



HYDROGEN TRANSPORT AND OXIDATIVE PHOSPHORYLA- 

 TION. The oxidations which occur in glycolysis, in 

 pyruvic and fatty acid oxidations, and in the re- 

 actions of the tricarboxylic acid cycle are enzymatic 



dehydrogenations. As noted pre\'iously, the hydrogen 



