Aharonowitz Y, Cohen G, Martin J F
George S. Wise Faculty of Life Sciences, Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Ramat Aviv, Israel.
Annu Rev Microbiol. 1992;46:461-95. doi: 10.1146/annurev.mi.46.100192.002333.
Penicillins and cephalosporins are produced by a wide variety of microorganisms, including some filamentous fungi, many gram-positive streptomycetes, and a few gram-negative unicellular bacteria. All produce these beta-lactam antibiotics by essentially the same biosynthetic pathway. Recently, most of the penicillin and cephalosporin biosynthetic genes have been cloned, sequenced, and expressed. The biosynthetic genes code for enzymes that possess multifunctional peptide synthetase, cyclase, epimerase, expandase, hydroxylase, lysine aminotransferase, and acetyltransferase activities and are organized in chromosomal gene clusters and coordinately expressed. DNA hybridization screens of streptomycetes demonstrate that beta-lactam biosynthetic genes may be more widespread in nature than is indicated by conventional antibiotic screens. They offer the possibility of expanding the search for organisms with potential to make new beta-lactam antibiotics. Attempts to improve current yields of beta-lactams in production strains by introducing into them additional copies of biosynthetic genes have been partially successful. Comparative sequence analysis of bacterial and fungal beta-lactam biosynthetic genes show they share very high sequence identity. A model that explains the similarity of biosynthetic genes from an evolutionary standpoint assumes horizontal gene-transfer between the two groups of organisms. Indirect evidence suggests the transfer occurred from the bacteria to the fungi.
青霉素和头孢菌素由多种微生物产生，包括一些丝状真菌、许多革兰氏阳性链霉菌以及少数革兰氏阴性单细胞细菌。所有这些微生物通过基本相同的生物合成途径产生这些β-内酰胺抗生素。最近，大多数青霉素和头孢菌素生物合成基因已被克隆、测序和表达。生物合成基因编码具有多功能肽合成酶、环化酶、差向异构酶、扩环酶、羟化酶、赖氨酸氨基转移酶和乙酰转移酶活性的酶，这些酶被组织在染色体基因簇中并协调表达。对链霉菌的DNA杂交筛选表明，β-内酰胺生物合成基因在自然界中的分布可能比传统抗生素筛选所显示的更为广泛。它们为扩大寻找具有产生新β-内酰胺抗生素潜力的生物体提供了可能性。通过向生产菌株中引入额外的生物合成基因拷贝来提高当前β-内酰胺产量的尝试已取得部分成功。对细菌和真菌β-内酰胺生物合成基因的比较序列分析表明，它们具有非常高的序列同一性。一个从进化角度解释生物合成基因相似性的模型假定两组生物体之间存在水平基因转移。间接证据表明这种转移是从细菌转移到真菌。
