Q.Insulin in the human body is secreted by pancreas as prohormone/proinsulin. The schematic polypeptide structure of proinsulin is given below. This proinsulin needs to undergo processing before it becomes functional in the body. Answer the questions that follow :

Concept: Post-translational processing of proinsulin into active insulin.

(a) During processing, proinsulin undergoes proteolytic cleavage — the C-peptide (connecting region) is removed, releasing the functional insulin molecule composed of two separate polypeptide chains (A-chain and B-chain).

(b) Eli Lilly used recombinant DNA technology (specifically, the chemical synthesis of genes for the A and B chains, inserted into E. coli plasmids for separate expression, followed by purification and in vitro combination). …

The Concept: Why Proinsulin Needs Processing

Insulin is a peptide hormone that regulates blood glucose levels. It is initially synthesised as a single, longer polypeptide chain called proinsulin — an inactive precursor (prohormone). This proinsulin has three segments: an A chain, a B chain, and a connecting C-peptide (the middle portion). The C-peptide keeps the A and B chains aligned correctly during folding, but it must be removed for the molecule to become biologically active. Without this cleavage, the insulin cannot bind properly to its receptor.

The processing is a classic example of post-translational modification — a common strategy in biology to prevent a potent molecule from acting prematurely inside the cell where it is made.

Step-by-Step Solution

(a) State the change the proinsulin undergoes at the time of its processing to become functional.

1. Proinsulin is a single polypeptide chain with three regions: B chain (at the N-terminus), C-peptide (middle), and A chain (at the C-terminus). The C-peptide connects the B and A chains.

2. During processing inside the pancreatic beta cells, specific proteolytic enzymes (prohormone convertases) cleave the proinsulin molecule at two sites — between the B chain and C-peptide, and between the C-peptide and A chain.

3. The C-peptide is excised and removed, leaving two separate polypeptide chains: the B chain (30 amino acids) and the A chain (21 amino acids).

4. These two chains remain associated through disulfide bonds (see part c), forming the mature, functional insulin molecule.

Answer for (a): The proinsulin is cleaved to remove the C-peptide, yielding the separate A and B chains that form the active insulin.

(b) Name the technique the American company Eli Lilly used for the commercial production of human insulin.

1. Before the 1980s, insulin for diabetic patients was extracted from the pancreases of pigs and cows (porcine and bovine insulin). These were slightly different from human insulin and could cause allergic reactions in some patients.

2. Eli Lilly partnered with the biotech company Genentech to produce the first recombinant human insulin, approved in 1982 under the brand name Humulin.

3. The technique used is recombinant DNA technology (also called genetic engineering). Specifically, they inserted the human insulin gene (or separately the A-chain and B-chain genes) into E. coli bacteria. The bacteria were then cultured in large fermentation tanks, where they expressed and produced the human insulin chains. These chains were purified and combined to form the active insulin.