Amino acid side-chain diversity

Proteins are the indispensable agents of biological function, and amino acids are the building blocks of proteins. The stunning diversity of the thousands of proteins found in nature arises from the intrinsic properties of only 20 commonly occurring amino acids. These features include (1) the capacity to polymerize, (2) novel acid-base properties, (3) varied structure and chemical functionality in the amino acid side chains, and (4) chirality. This chapter describes each of these properties, laying a foundation for discussions of protein structure (Chapters 5 and 6), enzyme function (Chapters 14-16), and many other subjects in later chapters. 

Evolution has provided the cell with a repertoire of 20 amino acids to build proteins. The diversity of amino acid side chain properties is enormous, yet many additional functional groups have been selectively chosen to be covalently attached to side chains and this further increases the unique properties of proteins. Diese additional groups play a regulatory role allowing the cell to respond to changing cellular conditions and events. Known covalent modifications of proteins now include phosphorylation, methylation, acetylation, ubi-quitylation, hydroxylation, uridylylation and glycosyl-ation, among many others. Intense study in this field has shown the addition of a phosphate moiety to a protein... 

Piperazines and derivatives are archaetypical scaffolds and can be considered as efficient, however, structurally simple peptidomimics. The scaffolds combine conformational rigidity with peptide-like spacial placement of amino acid side chains or isosteres thereof. Moreover, piperazines can be used to confine compounds with beneficial properties such as water solubihty. Piperazines are therefore in the center of synthetic interest and many different synthetic pathways have been designed [16-19]. A preferred way to synthesize different piperazine scaffolds with plenty of variabihty provides MCR chemistry. Several piperazine scaffolds are currently only accessible by isocyanide-based MCR. Likely they could be assembled by sequential synthesis as well however, the synthetic efficiency, the diversity, and the size of the alternative chemical space will be inferior. The application of... 

A wide variety of chromatographic operation modes exists for the separation of proteins, due to the variation in their behavior. The diverse biological and biochemical functions of proteins originate largely from differences in the amino acid side chains that convey different properties onto the protein. This provides the protein analysts with a guide to select the possible operation modes. Possible techniques are ... 

The term molybdenum cofactor (or Moco) refers to the metal center and its inner coordination sphere. Moco is not a single, unique, moiety, rather it is a diverse collection of protein-bound sites that have certain common features. Thus, one or two MPTs are coordinated to the metal via the dithiolene group and the remainder of the metal s coordination sphere is taken up by non-protein ligands (e.g., oxo, hydroxo, water, or sulfido groups) and, in some cases, an amino acid side chain is coordinated. Hille (1) has shown that the mononuclear Mo—MPT enzymes of molybdenum can be classified into three families, on the basis of the nature of the inner coordination sphere of the oxidized form of the enzyme (Fig. 2). 

What is the biologic significance of diversity in amino acid side chains The amino acid sequence is the blueprint for protein structure. Consequently, the complexity of protein structures is a function of the variety and the length of the sequences... 

In the protein world structural conservatism and diversity are combined on two different levels conservatism in the more macroscopic, that is, the structural level and diversity on the microscopic level, that is, the individual amino acid sequence. The fold defines the scaffold of the protein, that is, the 3D structure of the amino acid backbone, as well as the shape and size of the active site and the spatial orientation of the catalytic residues. The individual amino acid side chains forming the active site and its catalytic residues determine the molecular interactions between the protein and the ligand. The same fold can be assembled by amino acid sequences with only as little as a few percent sequence similarity. Thus both, fold and sequence, determine together the binding properties of any protein and enable the vast number of specific functions to be carried out by a limited number of fold types. ... 

Since proteins are polymers of amino acids, the chemical nature of the amino acid side chains and the order of the amino acids play an important role in establishing the biological properties of the active protein. Proteins may differ from each other according to size, charge density, shape and biological activity. Similarly, protein purification schemes require a similar diverse combination of separation techniques based on the various physicochemical properties of proteins. 

Substrate binding at the active site [8] plays a crucial role in protease-catalyzed peptide bond formation. Unfortunately, a simple C-N ligase is not capable of developing different substrate binding regions, for example by induced fit, for the structurally diverse amino acid side chain functionalities. According to Linus Pauling the action of an enzyme depends on the complementarity of the active site to the transition state structure of a reaction, as shown in Scheme 2 for peptide bond formation. 

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