# Recent Advances in Biocatalysis for Drug Synthesis
## 2 Biocatalysis for Drug Synthesis  
### Expansion of Product Spectrum  
#### 2.1.1 Natural Metabolism as Source of Enzymes and Biochemical Pathways  
Primary metabolism maintains all functions of life, including energy balance, growth, reproduction, as well as reaction to internal and external stimuli. However, such conditions are rarely found in ecosystems. Species have to deal with source limitations, abiotic stresses, and biotic interactions ranging from mating to defeating predators. The ability of a species to occupy a particular ecological niche or to adapt to unfavorable conditions is, in many respects, conferred by secondary metabolism. While the variety of primary metabolism pathways is rather limited in terms of numbers, and to some extent general to most species, secondary metabolism is as diverse as the immeasurable number of species themselves. Humans have used natural substances as privileged structures, with regard to their biological activity, more or less consciously for thousands of years, with substances such as spices or colors, but above all as pharmacological agents. However, this use was often limited to extraction from the natural producer and access to effective derivatives was often difficult. Developments in recent decades, such as genome mining, synthetic DNA technologies, and the constructive convergence of chemical and biological methods, are now opening up more intensive and productive access to natural substances, also by enzymological or heterologous means [10]. Although the number of secondary metabolites is almost immeasurable, the secondary metabolic pathways run in a similar way (Figure 1). The precursor molecules such as acetyl-CoA, amino acids or glycosides are taken from the primary metabolism, and in one enzymatic step or a few steps, the basic structure of the natural substance is formed [11]. For example, a terpene cyclase produces terpene backbones [12], polyketide synthase machinery produces polyketide structures [13] or the phenylpropanol metabolic pathway starts with the formation of cinnamic acid derivatives by phenylalanine/tyrosine ammonia lyase (PAL/TAL) [14]. Starting from these basic scaffolds, many natural product derivatives are then decorated in vivo by late-stage decorations, such as the introduction of functional groups (oxyfunctionalization, glycosylation, halogenations, etc.) or the conversion of existing functional groups (eliminations, oxidations/reductions, substitutions). From a synthetic point of view, this scheme might be attractive at any stage: (I) Applying the entire pathway or reprogramming it to produce a particular natural compound and congeners by means of biosynthesis, semisynthesis, and mutasynthesis, respectively. (II) Applying the scaffold key enzyme(s) in a biocatalytic manner to get access to complex natural compounds including sophisticated C-C-couplings or the formation of stereogenic elements [10]. In addition, the last stage, namely the late-stage decorations (III), are attractive to be applied for introducing or modifying functional groups. In particular, the third strategy is instrumental in generating derivate libraries as it is carried out in nature. In contrast to primary metabolism, the enzymes from secondary metabolism are often intentionally promiscuous [15]. Thus, a common task in using the enzymes of secondary metabolism is to narrow down the substrate spectrum, whilst, for enzymes of primary metabolism, the substrate specificity must be altered or widened. Here we highlight some of the most recent developments to add to the portfolio of biocatalytic synthesis of APIs (Table 1).