Biosynthesis of Branched-Chain Compounds 25 



a more highly oxidized 4-carboo compound taking the place of aceto- 

 acetate. It is improbable that this hypothetical precursor of branched 

 amino acids in Neurospora (111) is a source of isoprenoid intermedi- 

 ates, since precursors other than acetate enter into its formation. 



It was fortunate that concurrently with the interest in branched- 

 chain intermediates hydroxymethylglutarate (HMG) was identified as 

 a constituent of various plants. 1 " 11 At the same time it was recalled 

 that acids such as /?-dimethylacrylic acid (DMA) , isovaleric acid ( IV ) , 

 and /^-hydroxyisovaleric acid (HIV) are to be found in nature, and 

 hence the moment seemed propitious for an inquiry into their origin 

 and possible relation to isoprene and steroid biosynthesis. With the 

 aid of the now widely used carrier technique the formation of the 

 above-mentioned acids from labeled acetate in animal tissues could 

 be readily demonstrated. 12,13 Moreover, the number and spacing of 

 the carbon atoms of acetate in the branched molecules conformed, 

 where investigated, 1 - with the pattern that had been predicted for the 

 hypothetical steroid precursor. So far, the postulated initial step which 

 leads to a branched compound, i.e., the condensation of acetate and 

 acetoacetate (or their coenzyme derivatives) to a 6-carbon dicarboxylic 

 acid has been elusive, although the reverse reaction has been shown 

 to occur. 



Considerable light has been thrown on the interrelationship of the 

 various branched-chain compounds by the discovery of Coon 14 > 15 that 

 in the conversion of the 5-carbon acids to acetoacetate a fixation of 

 carbon dioxide is an integral part of the overall process suggesting the 

 sequence of steps shown in Fig. 1. Some of these reactions are closely 



i+co 2 

 CH 3 H 3 C OH 



\ T \| 



CO + CH 3 COOH ^± C— CH 2 COOH 



/ / HMG 



CH 2 OH 2 



I. I 



COOH COOH 



Fig. I. 



