232 Chapter 8 Industrial production of amino acids by fermentation and chemo-enzymatic methods 8.1 Introduction Amino acids have always played animportant role in the biology of life, in biochemistry and in (industrial) chemistry. There are several reasons why they are of commercial amino acids are the building blocks of proteins and they play an essential role in the regulation of the metabolism of living organisms. Large-scale essential chemical and microbial producton processes have been commercialised for a number no aads of essential amino acids The use of glutamic acid lysine and methionine as food and feed additives is well established nowadays. Secondly, current interest in developing on-proteino. peptide-derived chemotherapeutics has heightened the importance of rare and genic amino non-proteinogenic pure amino acids. For example, D-phenylglycine and acds D-p-hydroxy-phenylglycine are building blocks for the broad spectrum B-lactam antibiotics ampicillin and amoxycillin, respectively. The natural amino acid L-valine is used as feedstock in the fermentative production of the cyclic peptide cyclosporin A, which has immuno-suppressive activity and is used in human transplant surgery Thirdly, amino acids are versatile chiral (optically active)building blocks for a whole range of fine chemicals. In the last two decades, there has been a growing public precursors for awareness and concern with regard to the exposure of man and his environment to an fine chemical ever increasing number of chemicals. The benefits, however, arising from the use synthesis therapeutic agents, pesticides, food and feed additives, etc are enormous. hence there is still an ever increasing demand for more selective drugs and pesticides which are targeted in their mode of action, exhibit less toxic side-effects and are more environmentally acceptable. To this end a central role will be played by chiral compounds, as nature at the molecular level is intrinsically chiral. Consequently, this provides an important stimulus for companies to market chiral products as pure optical isomers. This in turn results in an increasing need for efficient methods for the industrial synthesis of optically active compounds Amino acids are, therefore, important as nutrients (food and feed ), as seasoning flavourings and starting material for pharmaceuticals, cosmetics and other chemicals They can be produced in a variety of ways(see Table 8.1) · chemical synthesis; isolation from natural materials(extraction) amino acid fermentations(using micro-organisms); chemo-enzymatic methods In this chapter we consider amino acid production by fermentation and by chemo-enzymatic methods. we first consider the stereochemistry of amino acids and the importance of chirality in chemical synthesis. General approaches to amino acid fermentation and recovery of amino acids from fermentation broths are then dealt with followed by a detailed consideration of the production of L-phenylalanine by direct fermentation. Later in this chapter, chemo-enzymatic methods of amino acid232 Chapter 8 essential ammo adds non-pcoteino￾genic amino acids precursors for me chemical synthesis Industrial production of amino acids by fermentation and cherno-enzymatic methods 8.1 Introduction Amino acids have always played an important role in the biology of life, in biochemistry and in (industrial) chemistry. There are several reasons why they are of commercial interest. Firstly, amino acids are the building blocks of proteins and they play an essential role in the reguiation of the metabolism of living organisms. Largescale chemical and microbial production processes have been commercialised for a number of essential amino acids. The use of glutamic acid, lysine and methionine as food and feed additives is well established nowadays. Secondly, current interest in developing peptide-derived chemotherapeutics has heightened the importance of rare and non-proteinogenic pure amino acids. For example, D-phenylglycine and D-phydroxy-phenylglycine are building blocks for the broad spectrum f3-ladam antibiotics ampicillin and amoxycillin, respectively. The natural amino acid L-valine is used as feedstock in the fermentative production of the cyclic peptide cyclosporin A, which has immuno-suppressive activity and is used in human transplant surgery. Thirdly, amino acids are versatile chiral (optically active) building blocks for a whole range of fine chemicals. In the last two decades, there has been a growing public awareness and concern with regard to the exposure of man and his environment to an ever increasing number of chemicals. The benefits, however, arising from the use of therapeutic agents, pesticides, food and feed additives, etc are enormous. Hence there is still an ever increasing demand for more selective drugs and pesticides which are targeted in their mode of action, exhibit less toxic side-effects and are more environmentally acceptable. To this end a central role will be played by chiral compounds, as nature at the molecular level is intrinsically chiral. Consequently, this provides an important stimulus for companies to market chiral products as pure optical isomers. This in turn results in an increasing need for efficient methods for the industrial synthesis of optically active compounds. Amino acids are, therefore, important as nutrients (food and feed), as seasoning, flavourings and starting material for pharmaceuticals, cosmetics and other chemicals. They can be produced in a variety of ways (see Table 8.1): 0 chemical synthesis; 0 isolation from natural materials (extraction); amino acid fermentations (using micro-organisms); 0 chemo-enzymatic methods. In this chapter we consider amino acid production by fermentation and by chemoenzymatic methods. We first consider the stereochemistry of amino acids and the importance of chirality in chemical synthesis. General approaches to amino acid fermentation and recovery of amino acids from fermentation broths are then dealt with, followed by a detailed consideration of the production of L-phenylalanine by direct fermentation. Later in this chapter, chemo-enzymatic methods of amino acid