Topoisomerases: A Biochemical Overview

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Function

During DNA replication and repair, chromosomes can become entangled. In order to prevent cytotoxic or mutagenic DNA strand breaks, Topoisomerase can disentangle DNA segments and add or remove supercoils. Several different types of Topoisomerase exist, which can be categorized into type I or type II, depending on whether they cut one or two strands of DNA. Both types contain the nucleophilic tyrosine, which is used to promote strand scission. [5]

Type I Mechanisms:

-Type IA and II attach to 5’ ends of DNA, then pass a single stranded segment of DNA through a transient break in a second single strand of DNA

-Type IB and IC attach to 3’ ends of DNA, then nick one DNA strand, which allows one duplex end to rotate around the remaining phosphodiester bond

Type II Mechanism:

Cleave both strands of a duplex DNA strand and pass another duplex DNA strand through the transient break

Disease

Relevance

Structural highlights

The primary structure of TOP1 can be divided into three regions. First, the N-terminus contains 214 amino acids, the core region contains 498 amino acids, and the C-terminus contains 53 amino acids. TOP1 consists of a multitude of various amino acids, but the active site consists of tyrosine residues in the C-terminus.

The secondary structure consists of right-handed alpha helices and antiparallel beta strands, which makes up beta sheets. The enzyme consists of 11 alpha helices and 12 beta strands. The clustering of beta sheets in this particular structure of TOP1 creates 3 beta sheets.

The tertiary structure consists of several motifs and domains. The motifs present are alpha bundles, alpha non-bundles, beta rolls, and beta ribbons. The domain consists of five residues of tyrosine and is a loop-like shape. This loop serves as the active site for the change in conformation, which allows for DNA helices entry.

The oligomeric state of the quaternary structure is heterotetrameric. There is no symmetry in this particular enzyme, due to the presence of various distinct subunits.

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