乙型肝炎病毒 (HBV) 是一种嗜肝、部分双链 DNA 病毒,通过逆转录复制,是慢性肝病和肝细胞癌的主要原因。逆转录由具有蛋白质引发、RNA 和 DNA 依赖性 DNA 合成(即逆转录酶)和核糖核酸酶 H 活性的四结构域多功能 HBV 聚合酶 (P) 蛋白催化。 P 也可能促进逆转录过程中发生的三链转移,它可能参与 HBV 的免疫逃避。逆转录由 P 氨基末端结构域中的酪氨酸残基引发,并且 P 在整个逆转录过程中保持共价连接到产物 DNA 上。 P 的逆转录酶活性是主导 HBV 治疗的核苷(酸)类似物药物的目标,而 P 是开发针对逆转录酶和核糖核酸酶 H 活性的新药物的持续努力的目标。尽管 P 催化了不寻常的逆转录途径以及 P 对 HBV 治疗的重要性,但由于研究酶的大量技术挑战,对 HBV P 的酶学和结构的了解严重滞后于逆转录病毒逆转录酶。更好地了解 P 将拓宽我们对自然界中逆转录元素多样性的认识,并将有助于改善对慢性 HBV 感染者的治疗。
The hepatitis B virus polymerase
Daniel N Clark 1 , Razia Tajwar 2 , Jianming Hu 3 , John E Tavis 4
Affiliations
Affiliations
1
Department of Microbiology, Weber State University, Ogden, UT, United States.
2
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, United States.
3
Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA, United States.
4
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, United States. Electronic address: [email protected].
PMID: 34861937 DOI: 10.1016/bs.enz.2021.06.010
Abstract
Hepatitis B virus (HBV) is a hepatotropic, partially double-stranded DNA virus that replicates by reverse transcription and is a major cause of chronic liver disease and hepatocellular carcinoma. Reverse transcription is catalyzed by the four-domain multifunctional HBV polymerase (P) protein that has protein-priming, RNA- and DNA-dependent DNA synthesis (i.e., reverse transcriptase), and ribonuclease H activities. P also likely promotes the three strand transfers that occur during reverse transcription, and it may participate in immune evasion by HBV. Reverse transcription is primed by a tyrosine residue in the amino-terminal domain of P, and P remains covalently attached to the product DNA throughout reverse transcription. The reverse transcriptase activity of P is the target for the nucleos(t)ide analog drugs that dominate HBV treatment, and P is the target of ongoing efforts to develop new drugs against both the reverse transcriptase and ribonuclease H activities. Despite the unusual reverse transcription pathway catalyzed by P and the importance of P to HBV therapy, understanding the enzymology and structure of HBV P severely lags that of the retroviral reverse transcriptases due to substantial technical challenges to studying the enzyme. Obtaining a better understanding of P will broaden our appreciation of the diversity among reverse transcribing elements in nature, and will help improve treatment for people chronically infected with HBV.
Keywords: Enzymology; Hepatitis B virus; Polymerase; Protein-priming; Reverse transcription; Ribonuclease H.