Research Institute of Molecular and Cellular Medicine, People's Friendship University of Russia (RUDN University), 117198 Moscow, Russia; N.N. Blokhin National Medical Research Center of Oncology of Ministry of Health of Russian Federation, 115478 Moscow, Russia.
Moscow Institute of Physics and Technology, 141701 Moscow region, Russia.
Biochim Biophys Acta Rev Cancer. 2024 Jul;1879(4):189122. doi: 10.1016/j.bbcan.2024.189122. Epub 2024 May 23.
Cancer cells are addicted to L-methionine (L-Met) and have a much greater requirement for L-Met than normal cells due to excess transmethylation, termed the Hoffman effect. By targeting this vulnerability through dietary restriction of L-Met, researchers have been able to achieve promising results in inhibiting tumor growth and eradicating cancer cells. Methioninase (EC 4.4.1.11; METase) catalyzes the transformation of L-Met into α-ketobutyrate, ammonia, and methanethiol. The use of METase was initially limited due to its poor stability in vivo, high immunogenicity, and enzyme-induced inactivating antibodies. These issues could be partially resolved by PEGylation, encapsulation in erythrocytes, and various site-directed mutagenesis. The big breakthrough came when it was discovered that METase is effectively administered orally. The enzyme L-asparaginase is approved by the FDA for treatment of acute lymphoblastic leukemia. METase has more potential as a therapeutic since addiction to L-Met is a general and fundamental hallmark of cancer.
癌细胞对 L-蛋氨酸（L-Met）上瘾，由于过度转甲基化，即霍夫曼效应，癌细胞对 L-Met 的需求比正常细胞大得多。通过饮食限制 L-Met 来针对这种脆弱性，研究人员已经能够在抑制肿瘤生长和消除癌细胞方面取得有希望的结果。甲硫氨酸酶（EC 4.4.1.11；METase）催化 L-Met 转化为α-酮丁酸、氨和甲硫醇。最初，由于 METase 在体内稳定性差、免疫原性高以及酶诱导的失活抗体，其应用受到限制。通过聚乙二醇化、红细胞包封和各种定点突变可以部分解决这些问题。当发现 METase 可以有效地口服给药时，这是一个重大突破。FDA 已批准酶 L-天冬酰胺酶用于治疗急性淋巴细胞白血病。METase 作为一种治疗方法具有更大的潜力，因为对 L-Met 的依赖是癌症的普遍和基本特征。
