ABSTRACT
The amino acid phenylalanine is currently manufactured worldwide at an annual scale exceeding 12,000 metric tons. The vast majority of this material is l-phenylalanine synthesized specifically for incorporation into the dipeptide sweetener aspartame. Production of l-phenylalanine grew rapidly during the 1980s in parallel with the demand for aspartame and has grown steadily in recent years. lphenylalanine is also used in food and medical applications, and demand is increasing in pharmaceutical development as a chiral intermediate or as a precursor of chiral auxiliaries such as benzyloxazolidinone. In contrast, only a few metric tons of d-phenylalanine are used annually, again in pharmaceutical drug development, although this application is increasing. Over the past two decades, a number of manufacturers have developed chemoenzymatic and purely biological routes for l-phenylalanine manufacture (Table 1). Chemoenzymatic syntheses have relied on resolution technology, applied to chemically prepared racemic phenylalanine derivatives or d,l-5-monosubstituted hydantoins and biotransformation routes from chemically prepared achiral precursors of l-phenylalanine. Purely biological routes have concentrated on the direct synthesis of l-phenylalanine through microbial fermentation means. Today, the largest and most commercially successful synthetic routes for l-phenylalanine production use large-scale fermentation of bacterial strains that overproduce l-phenylalanine. Such microorganisms have been isolated through a combination of classical mutagenesis selec-
TABLE 1 Commercial Processes for l-Phenylalanine Synthesis
l-Phenylalanine processes Company developed
Ajinomoto Microbial fermentation Biotechnica Microbial fermentation Degussa/Rexim Enzymatic resolution (amino-
acylase) DSM Enzymatic resolution (amino
acid amidase) Genex Biotransformation (phenylala-
nine ammonia lyase) Kyowa Hakko Microbial fermentation Miwon Microbial fermentation Nutrasweet Co. Microbial fermentation, bio-
transformation (aminotransferase)
PEI Biotransformation (aminotransferase)
Tanabe Seiyaku Enzymatic resolution, biotransformation (aminoacylase, aminotransferase)
tion procedures and molecular genetic manipulation, the latter being derived from a detailed understanding of the molecular biology of the pathways involved in bacterial l-phenylalanine biosynthesis. Conversely, the present commercial production of d-phenylalanine relies solely on chemoenzymatic resolution.
