1-A. Sequence of amino acids in proteins

Protein structure is studied as the primary, secondary, tertiary and quaternary levels (Box 1). Primary structure denotes the number and sequence of amino acids in the protein. The higher levels of organisation are decided by the primary structure. Each polypeptide chain has a unique amino acid sequence decided by the genes. The primary structure is maintained by the covalent peptide bonds (Fig.1).

BOX1. Definitions of Levels of Organization

Fig1. Peptide bond formation

Students should have a clear concept of the term "sequence". See the following example:

Gly - Ala - Val (1)

Gly - Val - Ala (2)

Both the tripeptides shown above contain the same amino acids; but their sequence is altered. When the sequence is changed, the peptide is also different.

1-B. Characteristics of a Peptide Bond

i. The peptide bond is a partial double bond.

ii. The C–N bond is ‘trans' in nature and there is no freedom of rotation because of the partial double bond character. (Fig. 2)

Fig2. Peptide bond is a partial double bond

iii. The distance is 1.32Å which is midway between single bond (1.49 Å) and double bond (1.27Å).

iv. The side chains are free to rotate on either side of the peptide bond.

 v. The angles of rotation known as Ramachandran angles, therefore determine the spatial orientation of the peptide chain (Fig. 3). (Dr GN Ramachandran did pioneering work on the structural aspects of proteins during 1950s and 1960s).

Fig3. Angles of rotation in a peptide bond

1-C. Numbering of Amino Acids in Proteins

 i. In a polypeptide chain, at one end there will be one free alpha amino group. This end is called the amino terminal (N-terminal) end and the amino acid contributing the alpha amino group is named as the first amino acid. (Fig. 4).

Fig4. End groups of polypeptide chain

ii. Usually the N-terminal amino acid is written on the left-hand side when the sequence of the protein is denoted. Incidentally, the bio synthesis of the protein also starts from the amino terminal end.

iii. The other end of the polypeptide chain is the carboxy terminal end (C-terminal), where there is a free alpha carboxyl group which is contributed by the last amino acid (Fig. 4). All other alpha amino and alpha carboxyl groups are involved in peptide bond formation.

iv. Amino acid residues in polypeptides are named by changing the suffix "-ine" to "-yl", for example, Glycine to Glycyl. Thus, peptide bonds formed by carboxyl group of glycine with amino group of Alanine, and then carboxyl group of Alanine with amino group of Valine and is called glycyl alanyl-valine and abbreviated as NH2-Gly-Ala-Val-COOH or Gly-Ala-Val or simply as GAV

1-D. Branched and Circular Proteins

 i. Generally, the polypeptide chains are linear. However, branching points in the chains may be produced by interchain disulphide bridges. The covalent disulphide bonds between different polypeptide chains in the same protein (interchain) or portions of the same polypeptide chain (intrachain) are also part of the primary structure.

 ii. Rarely, instead of the alpha COOH group the gamma carboxyl group of glutamic acid may enter into peptide bond formation, e.g. Glutathione (gamma-glutamyl-cysteinyl-glycine) . The term pseudopeptide (or isopeptide) is used to denote such a peptide bond formed by carboxyl group, other than that present in alpha position. iii. Very rarely, protein may be in a circular form, e.g. Gramicidin.

 1-E. Primary Structure of Insulin

As an example of the primary structure of a protein, that of insulin is shown in Fig. 5. This was originally described by Sanger in 1955 who received the Nobel prize in 1958.

Fig5. Primary structure of human insulin

i. Insulin has two polypeptide chains. The A chain (Glycine chain) has 21 amino acids and B (Phenyl alanine) chain has 30 amino acids.

 ii. They are held together by two interchain di sulphide bonds (Fig. 5). A chain 7th cysteine and B chain 7th cysteine are connected. similarly A chain 20th cysteine and B chain 19th cysteine are connected. There is another intrachain disulphide bond between 6th and 11th cysteine residues of A chain.

iii. The species variation is restricted to amino acids in position 8, 9 and 10 in A chain and in C-terminal of B chain (Fig. 5). The amino acid sequence has been conserved to a great extent during evolution.

 iv. The porcine insulin and human insulin are structurally similar, except the terminal amino acid in B chain (Thr → Ala) (Fig. 5). Bovine Insulin may produce antibodies in humans by repeated injections. But de-alaninated porcine Insulin, bearing no antigenic difference from human Insulin will not produce antibodies in diabetic patients even after a long-term use. Nowadays human Insulin is being produced by recombinant DNA technology.

1-F. Pro-insulin

Beta cells of pancreas synthesize insulin as a prohormone. Proinsulin is a single polypeptide chain with 86 amino acids. Biologically active insulin (2 chains) is formed by removal of the central portion of the pro-insulin before release. The C-peptide (connecting peptide) is also released into the circulation (Fig. 6).

Fig6. Conversion of Pro-insulin to active insulin. Arrows = site of action of proteolytic enzymes

1-G. Primary Structure Determines Biological Activity A protein with a specific primary structure, when put in solution, will automatically form its natural three dimensional shape. So the higher levels of organization are dependent on the primary structure. Even a single amino acid change (mutation) in the linear sequence may have profound biological effects on the function. For example, in HbA (normal hemoglobin) the 6th amino acid in the beta chain is glutamic acid; it is changed to valine in HbS (sickle cell anemia).

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مواضيع ذات صلة

Brown Adipose Tissue Promotes Thermogenesis

Hormones Regulate Fat Mobilization

Adipose Tissue is The Main Store of Triacylglycerol in The Body

Classification of Proteins

Precipitation Reactions of Proteins

Study of Protein Structure

Imbalance in the Rate of Triacylglycerol Formation & Export Causes Fatty Liver

The Liver Plays A Central Role in Lipid Transport & Metabolism

HDL Takes Part in Both Lipoprotein Triacylglycerol & Cholesterol Metabolism

Tertiary Structure of Proteins

Secondary Structure of Proteins

Chylomicrons & Very-low Density Lipoproteins are Rapidly Catabolized