Bphl, also known as biphenyl hydrolase-like protein, is a serine hydrolase. It catalyzes the hydrolytic activation of amino acid ester prodrugs of nucleoside analogs such as valacyclovir and valganciclovir [3,4]. It also acts as a homocysteine thiolactonase, detoxifying homocysteine thiolactone, a reactive metabolite associated with various diseases [6]. Additionally, it may be involved in neurodegeneration through its role in homocysteine metabolism [2]. Gene knockout mouse models can be valuable for studying its functions in vivo.

In a study on lung cancer cell lines, knockdown of Bphl led to decreased proliferation, colony formation, and metastasis, along with increased apoptosis and cell cycle alterations. In nude mouse tumor implantation models, Bphl knockdown also resulted in decreased tumor growth, indicating that Bphl potentially promotes tumor growth in lung cancer [1]. In Bphl knockout mice, valacyclovir was still rapidly and efficiently hydrolyzed to acyclovir, suggesting that Bphl is not obligatory for this conversion either presystemically or systemically [5].

In conclusion, Bphl has multiple functions including prodrug activation and homocysteine thiolactone detoxification. The use of gene knockout mouse models has revealed its potential role in promoting lung cancer growth and its non-obligatory role in valacyclovir conversion. These findings contribute to understanding Bphl's functions in specific disease areas such as lung cancer.

References:

1. Ren, Pengfei, Zhai, Jianxue, Wang, Xuelian, Cai, Kaican, Wang, Haofei. 2023. Inhibition of BPHL inhibits proliferation in lung carcinoma cell lines. In Translational lung cancer research, 12, 1051-1061. doi:10.21037/tlcr-23-225. https://pubmed.ncbi.nlm.nih.gov/37323178/

2. Jakubowski, Hieronim. 2024. Homocysteine Thiolactone Detoxifying Enzymes and Alzheimer's Disease. In International journal of molecular sciences, 25, . doi:10.3390/ijms25158095. https://pubmed.ncbi.nlm.nih.gov/39125665/

3. Kim, Insook, Crippen, Gordon M, Amidon, Gordon L. . Structure and specificity of a human valacyclovir activating enzyme: a homology model of BPHL. In Molecular pharmaceutics, 1, 434-46. doi:. https://pubmed.ncbi.nlm.nih.gov/16028355/

4. Kim, Insook, Song, Xueqin, Vig, Balvinder S, Lorenzi, Philip J, Amidon, Gordon L. . A novel nucleoside prodrug-activating enzyme: substrate specificity of biphenyl hydrolase-like protein. In Molecular pharmaceutics, 1, 117-27. doi:. https://pubmed.ncbi.nlm.nih.gov/15832508/

5. Hu, Yongjun, Epling, Daniel, Shi, Jian, Amidon, Gordon L, Smith, David E. 2018. Effect of biphenyl hydrolase-like (BPHL) gene disruption on the intestinal stability, permeability and absorption of valacyclovir in wildtype and Bphl knockout mice. In Biochemical pharmacology, 156, 147-156. doi:10.1016/j.bcp.2018.08.018. https://pubmed.ncbi.nlm.nih.gov/30121252/

6. Marsillach, Judit, Suzuki, Stephanie M, Richter, Rebecca J, Rettie, Allan E, Furlong, Clement E. 2014. Human valacyclovir hydrolase/biphenyl hydrolase-like protein is a highly efficient homocysteine thiolactonase. In PloS one, 9, e110054. doi:10.1371/journal.pone.0110054. https://pubmed.ncbi.nlm.nih.gov/25333274/