The bleomycins (BLMs) are widely used in combination therapies for the treatment of various cancers. Dose-dependent and cumulative pulmonary toxicity is the major cause of BLM-associated morbidity, limiting the broad uses of BLMs as anticancer drugs. The organ specificity of BLM-induced toxicity has been correlated with the expression of the hBLMH gene, encoding the human bleomycin hydrolase (hBLMH), which is poorly expressed in the lung. hBLMH hydrolyzes BLMs into the biologically inactive deamido BLMs, thereby protecting organs from BLM-induced toxicity. Here we report (i) expression of hBLMH and production and isolation of recombinant human bleomycin hydrolase (rhBLMH) from E. coli, (ii) structural characterization of deamido BLM A2 and B2 isolated from rhBLMH-catalyzed hydrolysis of BLM A2 and B2, and (iii) kinetic characterization of the rhBLMH-catalyzed hydrolysis of BLM A2 and B2, in comparison with five BLM analogues. rhBLMH from E. coli catalyzes rapid and efficient hydrolysis of all BLMs tested, exhibiting a superior catalytic efficiency for BLM B2. These findings reveal new opportunities to overcome BLM-induced pulmonary toxicity in chemotherapies, potentially by exploring BLM B2 as the preferred congener, engineering designer BLMs with optimized activity for rhBLMH, or co-administrating rhBLMH directly into the lung as a potential protein therapeutic.

博来霉素（BLM）被广泛用于治疗各种癌症的联合疗法中。剂量依赖性和累积性肺毒性是BLM相关发病率的主要原因，限制了BLM作为抗癌药物的广泛应用。BLM诱导的毒性的器官特异性已与编码人类博来霉素水解酶（hBLMH）的hBLMH基因的表达相关，后者在肺中的表达很差。hBLMH将BLM水解为具有生物活性的脱酰胺基BLM，从而保护器官免受BLM诱导的毒性的侵害。这里，我们报告（I）的表达hBLMH和从生产和重组人博莱霉素水解酶（rhBLMH）的隔离大肠杆菌，（ii）与五个BLM类似物相比，从rhBLMH催化的BLM A2和B2水解物中分离的脱酰胺基BLM A2和B2的结构表征，以及（iii）rhBLMH催化的BLM A2和B2水解的动力学特征。来自大肠杆菌的rhBLMH催化所有测试的BLM的快速有效水解，对BLM B2表现出优异的催化效率。这些发现揭示了克服化学疗法中BLM诱导的肺毒性的新机会，这可能是通过探索BLM B2作为首选同源物，对rhBLMH具有最佳活性的工程设计BLM或将rhBLMH直接作为一种潜在的蛋白质治疗剂共同施用到​​肺中来实现的。