5'-deoxy-5'-methylthioadenosine phosphorylase

Introduction

5'-Deoxy-5'-methylthioadenosine phosphorylase (MTAP) is an enzyme involved in the metabolism of the purine nucleoside derivative, 5'-deoxy-5'-methylthioadenosine (MTA). MTAP catalyzes the reversible phosphorolysis of MTA, converting it into adenine and 5-methylthio-D-ribose-1-phosphate.

The MTAP enzyme is primarily known for its role in the salvage pathway of methionine and adenine metabolism. MTA is a byproduct of polyamine biosynthesis and is also formed during the degradation of S-adenosylmethionine (SAM). By catalyzing the breakdown of MTA, MTAP helps to recycle adenine and 5-methylthio-D-ribose-1-phosphate, which can be further metabolized and utilized by the cell.

The MTAP gene is located on chromosome 9p21 and is often found in close proximity to the tumor suppressor gene CDKN2A (p16INK4a). Loss of heterozygosity (LOH) or deletion of the CDKN2A/MTAP locus is a common genetic alteration in several human cancers, including melanoma, lung cancer, and pancreatic cancer. This suggests that MTAP may have a tumor-suppressive role, and its inactivation or loss may contribute to tumorigenesis.

The potential tumor-suppressive function of MTAP has made it an interesting target for cancer therapy. In preclinical studies, the loss of MTAP has been associated with increased sensitivity to certain chemotherapeutic agents, and strategies to exploit this vulnerability are being explored.

In summary, 5'-deoxy-5'-methylthioadenosine phosphorylase (MTAP) is an enzyme involved in the metabolism of 5'-deoxy-5'-methylthioadenosine (MTA). It catalyzes the breakdown of MTA into adenine and 5-methylthio-D-ribose-1-phosphate. MTAP is often found in close proximity to the CDKN2A tumor suppressor gene and is implicated in tumorigenesis when its function is lost or impaired.

Function

MTAP catalyzes the reversible phosphorolysis of to adenine and 5-methylthio-D-ribose-1-phosphate. (PDB code 1cg6). Water molecule is shown as red sphere. MTAP is part of the polyamine metabolism. This reaction is the principle source of adenine in human cells. MTAP catalyzes the first step in the methionine salvage pathway.^[1]

Disease

MTAP is deficient in many cancers because it is co-deleted with the tumor suppressor p16.

Relevance

MTAP is a potential target of chemotherapy. More than 20% of human various cancer cells do not show MTAP activity.

3D structures of 5’-deoxy-5’-methylthioadenosine phosphorylase

5’-deoxy-5’-methylthioadenosine phosphorylase 3D structures