Feng J A, Crasto C J, Matsumoto Y
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Biochemistry. 1998 Jul 7;37(27):9605-11. doi: 10.1021/bi9808619.
DNA polymerase beta (Pol beta) is one of the key enzymes in the base excision repair pathway. The amino-terminal 8 kDa domain of Pol beta has an activity for excising a 5'-deoxyribose phosphate (dRP) group from preincised apurine/apyrimidine (AP) sites. Recent biochemical studies have identified the catalytic center of the 8 kDa domain and provided new insight into the mechanism of DNA repair by DNA polymerase beta. By incorporating both structural and biochemical data, we present here a reaction mechanism for the 5'-dRP excision activity of the 8 kDa domain. This mechanism focuses on a catalytic groove near the helix-hairpin-helix (HhH) motif of the 8 kDa domain. Our model shows that the dRP group of the AP site can be stabilized in the catalytic groove through extensive interactions with the residues of the groove and be positioned close to the active center, Lys72, which catalyzes a beta-elimination reaction by forming a Schiff base with the C1' of the dRP group.
DNA聚合酶β（Polβ）是碱基切除修复途径中的关键酶之一。Polβ的氨基末端8 kDa结构域具有从预先切割的无嘌呤/无嘧啶（AP）位点切除5'-脱氧核糖磷酸（dRP）基团的活性。最近的生化研究确定了8 kDa结构域的催化中心，并为DNA聚合酶β的DNA修复机制提供了新的见解。通过整合结构和生化数据，我们在此提出了8 kDa结构域5'-dRP切除活性的反应机制。该机制聚焦于8 kDa结构域螺旋-发夹-螺旋（HhH）基序附近的一个催化凹槽。我们的模型表明，AP位点的dRP基团可通过与凹槽残基的广泛相互作用稳定在催化凹槽中，并定位在靠近活性中心Lys72的位置，Lys72通过与dRP基团的C1'形成席夫碱催化β-消除反应。
