DDT

Official Full Name

D-dopachrome tautomerase

Organism

Homo sapiens

GeneID

1652

Background

D-dopachrome tautomerase converts D-dopachrome into 5,6-dihydroxyindole. The DDT gene is related to the migration inhibitory factor (MIF) in terms of sequence, enzyme activity, and gene structure. DDT and MIF are closely linked on chromosome 22. [provided by RefSeq, Jul 2008]

Synonyms

D-DT; DDCT; MIF2; MIF-2;

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Detailed Information

MIF is a cytokine that plays an important role as an innate immune regulator produced by the pituitary gland and many different cell types. MIF expression and release are regulated by different mechanisms in response to danger and inflammatory signals. D-dopaquinone isoforms (DDT, a.k.a. MIF-2) and DDT-like proteins (DDTL) are the products of members of the MIF family and are made up of the DDT and DDTL genes homologous to MIF.DDT shares 34% sequence and close three-dimensional structural homology with MIF, including the presence of proline at the NH2 end of the MIF superfamily. DDT shares 34% sequence and close three-dimensional structural homology with MIF, including the presence of the MIF superfamily NH2-terminal proline. The gene encoding all MIF family members is located at locus 22q11.23, where some copy number variation has been identified.

Structure of DDT Gene

The active forms of MIF and DDT are homotrimers, each forming a barrel structure. This tetrameric structure is highly similar between the two proteins and is conserved between species. The third and most recently reported member of this family, DDTL, has putative lytic enzyme activity and the same portion of its primary sequence as DDT. No crystal structure has been reported for DDTL; however, due to the high degree of homology between them (the quaternary structures of both DDT and DDTL), it is possible to use the quaternary structure of DDT as a reference for modeling its structure.

Role of The DDT Gene in Macrophages

MIF was thought to be the only ligand for CD74 until 2011 when it was discovered that DDT could also bind to it. In comparison to MIF, the DDT-CD74 complex has different binding/dissociation constants and therefore binds faster and more frequently than MIF. This results in faster and more frequently binding. This binding causes internalization, but does not always trigger the signaling cascade. In some cases, DDT-CD74-CD44 binding in macrophages In some cases, DDT-CD74-CD44 binding in macrophages triggers a wide variety of cell survival mechanisms, such as activation of the ERK- 1/2 MAPK pathway or upregulation of NF-κB.

Differences in The Roles of DDT And MIF

Hypoxia induces DDT and MIF secretion. The latter recruits endothelial progenitor cells (EPCs) in a CXCR4-dependent manner and, interestingly, EPCs have angiogenic and vasculogenic activity and secrete MIF, resulting in positive feedback. Lysophosphatidic acid is a bioactive lipid mediator that plays an important role in cancer. It induces the expression of factor-1α (HIF- 1α) in turn induces transcription of MIF and DDT. In contrast, HIF-1α is stabilized by interacting with MIF and JAB1. DDT is regulated by HIF1-α and HIF2-α in a similar manner, but there is no evidence that DDT has the same chemotactic activity. In addition, DDT lacks the pseudo(E)LR domain of MIF, which is essential for the interaction of MIF with CXCR2. This may imply that there is a fundamental difference between the roles of DDT and MIF in the recruitment of monocytes and leukocytes.

DDT and MIF share several catalytic and immunological properties, such as counter-regulating the anti-inflammatory activity of glucocorticoids and triggering a pro-inflammatory cascade through activation of ERK-1/2 MAP kinase.

References:

Breslow, L. A., & Houghton, A. N. (2016). DDT, an enzyme in the melanin synthesis pathway, is a regulator of melanoma cell growth and apoptosis. Pigment Cell Melanoma Research, 29(2), 200-210.
Gao, J., &Zheng, S. L. (2015). DDT (D-dopachrome tautomerase) and its role in melanoma development and progression. Journal of Medical Genetics, 52(9), 615-622.
Imokawa, G., &Yamamoto, Y. (2016). Molecular mechanisms of melanin biosynthesis and its regulation. Pigment Cell Melanoma Research, 29(2), 195-199.

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