DDT

DDT Full Name

D-dopachrome tautomerase

DDT Introduction

DDT encodes D-dopachrome tautomerase, a small protein that was first identified through its ability to catalyze the conversion of D-dopachrome into 5,6-dihydroxyindole, a reaction of uncertain physiological significance that nevertheless gave the enzyme its name. Modern research has reframed DDT as a cytokine-like mediator that belongs to a small family of proteins founded by macrophage migration inhibitory factor (MIF), to which DDT is structurally and functionally related; accordingly, it is also known as MIF-2. Like MIF, DDT is a secreted protein that possesses tautomerase enzyme activity but whose principal biological functions appear to be the regulation of inflammation and cell survival. DDT is expressed in a wide range of tissues and is induced by inflammatory stimuli, and it has been shown to activate signaling pathways that promote the survival of inflammatory cells, to counteract the anti-inflammatory actions of glucocorticoids, and to participate in the innate immune response to infection. Elevated levels of DDT have been measured in the blood and tissues of patients with inflammatory and autoimmune diseases, and the protein has been implicated in the pathogenesis of sepsis, arthritis, and other conditions. Because of its similarity to MIF, which is an established therapeutic target, DDT is also being investigated as a target for antibodies and small-molecule inhibitors that could dampen excessive inflammation.

Figure 1. The structure of DDT.

Tautomerase Fold and Relation to Macrophage Migration Inhibitory Factor
DDT is a small protein of roughly 13 kDa that assembles into a homotrimer, a quaternary structure that is unusual for a protein of its size.
Each subunit folds into a beta-sheet sandwich of the tautomerase superfamily, and the active sites are formed at the interfaces between adjacent subunits, with a conserved proline residue contributing the catalytic nucleophile.
The DDT gene is located on human chromosome 22 in the immediate vicinity of the MIF gene, and the two genes are thought to have arisen through an ancient duplication.
DDT and MIF share a common three-dimensional fold and both possess tautomerase activity toward non-physiological substrates such as D-dopachrome, but they differ in their potencies and in the details of their biological activities.
Like MIF, DDT is secreted from cells despite lacking a classical signal peptide, and it can enter cells through receptor-mediated uptake or act at the cell surface.
The tautomerase active site of DDT is also a binding site for small-molecule inhibitors, and compounds that covalently modify the catalytic proline have been shown to block the protein's biological activities.
The structural similarity between DDT and MIF has allowed the development of cross-reactive antibodies and inhibitors that target both proteins simultaneously.

Inflammatory Signaling, Immune Regulation, and Therapeutic Potential
DDT is induced by pro-inflammatory cytokines and microbial products, and it is secreted by immune cells where it acts in a cytokine-like manner to amplify inflammatory responses.
Functional studies have shown that DDT can activate the same signaling pathways as MIF, including the CD74-dependent activation of MAP kinases and the suppression of glucocorticoid-mediated anti-inflammatory effects.
By counteracting glucocorticoid action, DDT and MIF can sustain inflammation even in the presence of steroid hormones, a property that is relevant to steroid-resistant inflammatory disease.
Elevated DDT expression or circulating levels have been reported in patients with conditions such as sepsis, rheumatoid arthritis, and other inflammatory disorders, and in some studies DDT levels correlate with disease severity.
In animal models, neutralization of DDT with antibodies or inhibition of its active site reduces inflammation and improves outcomes in sepsis and other inflammatory challenges, supporting the protein as a therapeutic target.
Because DDT and MIF share functions and receptors, strategies that simultaneously block both proteins may be more effective than targeting either alone, and such dual inhibitors are under active development for inflammatory and autoimmune diseases.

Alternate Names for DDT

DDT; D-dopachrome tautomerase; D-dopachrome decarboxylase; D dopachrome decarboxylase; DDCT; D dopachrome tautomerase; DOPD_HUMAN; Phenylpyruvate tautomerase II; OTTHUMP00000198527; OTTHUMP00000198528