米多霉素生物合成机理的研究
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摘要
米多霉素是一类肽核苷类抗生素,具有强烈的抑制植物白粉病的活性。本研究利用来自杀稻瘟菌素生物合成基因簇上的胞嘧啶核苷单磷酸水解酶基因blsM及其同源基因设计兼并引物,从生裂链轮丝菌ZJU5119的基因组文库中筛选出六个相互重叠的柯斯质粒,其中柯斯质粒14A6可以使异源宿主变铅青链霉菌合成米多霉素,表明其包含了米多霉素生物合成所必须的全部基因。
对14A6进行序列测定,其插入序列全长43,561bp,通过FramePlot beta4.0预测,它包含41个开放阅读框。其中milA编码了胞嘧啶核苷单磷酸羟甲基化酶,敲除milA的生裂链轮丝菌突变株只产生去羟甲基米多霉素。MilB是BlsM的同源蛋白,milB的突变株丧失了产生米多霉素和去羟甲基米多霉素的能力。大肠杆菌融合表达的MilA蛋白能够专一的在胞嘧啶核苷单磷酸的C5位上引入羟甲基基团,而不接受胞嘧啶或胞嘧啶脱氧核苷单磷酸作为其底物;融合表达的MilB的酶动力学实验表明:它能够高效的水解羟甲基胞嘧啶核苷单磷酸成羟甲基胞嘧啶,同时也能够水解胞嘧啶核苷单磷酸形成胞嘧啶;在MilA和MilB共同作用下形成的羟甲基胞嘧啶和胞嘧啶的比例约为9:1,而生裂链轮丝的发酵产物中米多霉素的产量与去羟甲基米多霉素比例却只有3:1,这种不一致在UDP-葡萄糖醛酸转移酶MilC的动力学反应参数中得到了解释,MilC催化UDP-葡萄糖醛酸与胞嘧啶和羟甲基胞嘧啶反应的Kcat/Km分别为: 0.5250±0.0019和0.2719±0.0012,表明其对胞嘧啶有着更高的催化效率,这部分抵消了MilB对羟甲基胞嘧啶强烈的偏好性。
米多霉素生物合成中一个让人迷惑而又引人兴趣的问题是葡萄糖残基C6原子的来源。用稳定性同位素C13 6个碳原子全标记的精氨酸喂养生裂链轮丝菌,其发酵产物中发现了分子量为520的米多霉素,含量比本底水平增高5倍,而非标记的米多霉素分子量为514。同时,高分辨二级质谱数据中所有包含胍基侧链的断裂碎片都比未喂养的对应部分分子量增高了6,表明标记的6个碳原子在精氨酸或者其衍生物与葡萄糖醛酸缩合过程中全部保留了下来,脱羧反应去掉的是葡萄糖醛酸羧基碳。所以,米多霉素葡萄糖残基C6原子来源于精氨酸而不是葡萄糖。
为了系统的提出米多霉素完整的生物合成途径,我们结合异源表达和系统突变,首先确定了米多霉素生物合成基因簇的左右两个边界分别位于orf-1-milA与milQ-orf+1之间,对其中包括的17个orf一一进行突变,除了milL突变没有影响之外,证明其它的16个基因与米多霉素的生物合成相关。
milG编码的是一个新颖的Radical SAM家族蛋白,它是唯一一个氧化还原酶候选基因,负责羟甲基胞嘧啶葡萄糖醛酸C4位上羟基氧化成羰基,在milG突变株的发酵液中,中间产物羟甲基胞嘧啶葡萄糖醛酸大量积累,这充分证明了其功能就是负责这一步关键的催化反应,这也是第一次在核苷类抗生素生物合成中报道的新型氧化酶基因。分别敲除两个氨基糖苷类磷酸转移酶基因milE和milQ,突变株都丧失了产生米多霉素的能力,推测这两个磷酸转移酶可能负责糖上的C2-C3间双键的形成。可能编码天冬氨酸/酪氨酸/芳香族氨基酸类氨基转移酶的milM和编码二氢吡啶甲酸合酶的milN基因的突变株均不能够再产生米多霉素,MilM可能参与催化精氨酸α位的氨基转化成羰基而形成α-酮酸,而MilN则负责α-羰基与脱羧后的己糖碳负离子之间的缩合。编码degT/dnrJ/eryC1/strS类氨基转移酶的milD和编码可能的连接酶功能的milH突变株都丧失了产生米多霉素的能力,推测前者是负责C4位上羰基的转氨反应,后者负责将激活的丝氨酸连接到C4位的氨基上,形成类似肽键的酰胺键。而中断LuxR家族的转录调节因子基因milO也消除了米多霉素的生产,说明它可能是一个途径专一性的调节基因。MilJ显示与Ubiquitone的羟甲基化酶有一定的同源性,可能负责精氨酸的gamma羟化;而MilI可能负责了丝氨酸的活化;ABC transporter基因milP的突变株也不产米多霉素,它很可能是米多霉素的抗性基因;编码Major Facilitator Superfamily的基因milk的突变株还能够产生米多霉素,但产量降低,它可能与磷酸葡萄糖的转运有关。
Mildiomycin (MIL) is a peptidyl nucleoside antibiotic with strong activity against powdery mildew disease of plants. In present work, the degenerate primers were designed based on blsM, the gene of CMP hydrolase in the blsticidin S biosynthetic gene cluster, together with its homologues. With the primers, six overlapping cosmids were screened from the genomic library of Streptoverticillum rimofaciens ZJU5119. 14A6, one of them can confer Streptomyces lividans 1326 to produce MIL, implying that it contains all the essential genes for biosynthesis of MIL.
The insertion sequence of 14A6 was determined and assembled into 43,561bp on which 41 ORFs were predicted by FramePlot beta4.0. The mutant of milA, a gene encoding CMP hydroxymethylase, could produce only dehydroxymethyl MIL (dHM-MIL), while neither of MIL and dHM-MIL can be biosynthesized when milB, homolog of blsM was disrupted. Recombinant MilA was purified in E. coli and shown to specifically introduce a C-5 hydroxymethyl group on CMP but not able to accept either cytosine or dCMP as substrate. The kinetic parameters of recombinant MilB showed that it hydrolyzed hydroxymethyl-CMP to hydroxymethyl-cytosine (HMC) more efficiently than did CMP to cytosine. With the CMP as substrate, the ratio of free HMC to cytosine generated by MilB and MilA was ca. 9:1 in in vitro assays while the ratio of MIL to dHM-MIL was 3:1 in the extracted broth of Streptoverticillum rimofaciens. The inconsistence was partly compensated by the substrate bias of MilC, which can catalyse the coupling of the cytosine or HMC with UDP-glucuronic acid into cytosylglucuronic acid (CGA) or HMCGA, respectively. The Kcat/Km of MilC to cytosine and HMC were 0.5250±0.0019 and 0.2719±0.0012, respectively.
A puzzling and interesting question regarding MIL biosynthesis was the origin of C-6 in carboxyl group. Using the stable isotope labeled L-arginine (U-13C6) to feed Streptoverticillum rimofaciens, the productivity of MIL with a mass of 520, 6 increments than that without isotope incorporation, increased to 11% from 2% after feeding of labeled L-arginine. Q-TOF/MS analyses of the purified mildiomycin indicated that all the fragments containing the guanidino-side chain gave a mass increment of 6, indicating thet all of six carbon atoms of labeled L-arginine were kept after the coupling of L-arginine or its derivative with glucuronic acid moiety, namely, C6 was derived from L-arginine rather than sugar as the precursors of MIL.
To propose the complete biosynthetic pathway of MIL, the boundaries were firstly determined via systamtic gene disruption as well as end sequencing of six overlapped cosmids. Two boundaries were located within orf-1-milA and milQ-orf+1. All included genes within the boundary were disrupted individually, and 16 genes were demonstrated to be involved in the biosynthesis of MIL except for milL, of which knock-out caused no effect on production of MIL.
The gene of milG encodes a unique Radical SAM family protein and is the only oxidase candidate supposed to be in charge of the oxidation of the hydroxyl group to carbonyl group in C4 of the hydroxymethyl cytosylglucuronic acid. In accordance with this assumption, intermediate of HMCGA was accumulated highly in the milG mutant, strongly supporting the role of MilG as a novel oxidase.in this key step. This was the first report of Radical SAM protein as the oxidase in the biosynthesis of nucleoside antibiotics.
Disruption of milE and milQ, two aminoglycoside phosphotransferase genes, abolished the production of MIL; they are presumably involved in the double bond formation between C2 and C3 of the sugar moiety. The gene of milM and milN, encoding an aspartate/tyrosine/aromatic aminotransferase and a dihydrodipicolinate synthetase respectively, were disrupted, and neither resultant mutant could produce MIL. MilM was supposed to convertα-amino group of L-arginine to carbonyl group, and MilN sequentially catalyze the coupling of the carbonyl group in theα-ketonic acid with the carboanion in the decarboxylated hexose. Another aminotransferase gene, namely milD, encoding a degT/dnrJ/eryC1/strS aminotransferase, was considered to transfer amino group to the carbonyl group in the C-4 of sugar residue. MilH, the homologue of BlsK, might be in charge of the attachment of activated L-serine to C4 group of sugar moiety to form amide-like bond in the MIL biosynthesis.
The disruption of a LuxR family regulator gene, milO, abolished the production of MIL, suggesting MilO should be a pathway-specific positive regulator. MilJ shows some homology with the Ubiquitone hydroxylase and postulated to be responsible for the hydroxylation ofγ-carbon in arginine residue. MilI was supposed to be involved in the activivation of L-serine. The mutant of an ABC transporter gene, milP, which was considered as the resistance gene, could not produce the MIL; the mutant of milk, a Major Facilitator Superfamily gene, produced less MIL compared to the wild type. MilK was proposed to be involved in the transportation of phosphogluconate.
对14A6进行序列测定,其插入序列全长43,561bp,通过FramePlot beta4.0预测,它包含41个开放阅读框。其中milA编码了胞嘧啶核苷单磷酸羟甲基化酶,敲除milA的生裂链轮丝菌突变株只产生去羟甲基米多霉素。MilB是BlsM的同源蛋白,milB的突变株丧失了产生米多霉素和去羟甲基米多霉素的能力。大肠杆菌融合表达的MilA蛋白能够专一的在胞嘧啶核苷单磷酸的C5位上引入羟甲基基团,而不接受胞嘧啶或胞嘧啶脱氧核苷单磷酸作为其底物;融合表达的MilB的酶动力学实验表明:它能够高效的水解羟甲基胞嘧啶核苷单磷酸成羟甲基胞嘧啶,同时也能够水解胞嘧啶核苷单磷酸形成胞嘧啶;在MilA和MilB共同作用下形成的羟甲基胞嘧啶和胞嘧啶的比例约为9:1,而生裂链轮丝的发酵产物中米多霉素的产量与去羟甲基米多霉素比例却只有3:1,这种不一致在UDP-葡萄糖醛酸转移酶MilC的动力学反应参数中得到了解释,MilC催化UDP-葡萄糖醛酸与胞嘧啶和羟甲基胞嘧啶反应的Kcat/Km分别为: 0.5250±0.0019和0.2719±0.0012,表明其对胞嘧啶有着更高的催化效率,这部分抵消了MilB对羟甲基胞嘧啶强烈的偏好性。
米多霉素生物合成中一个让人迷惑而又引人兴趣的问题是葡萄糖残基C6原子的来源。用稳定性同位素C13 6个碳原子全标记的精氨酸喂养生裂链轮丝菌,其发酵产物中发现了分子量为520的米多霉素,含量比本底水平增高5倍,而非标记的米多霉素分子量为514。同时,高分辨二级质谱数据中所有包含胍基侧链的断裂碎片都比未喂养的对应部分分子量增高了6,表明标记的6个碳原子在精氨酸或者其衍生物与葡萄糖醛酸缩合过程中全部保留了下来,脱羧反应去掉的是葡萄糖醛酸羧基碳。所以,米多霉素葡萄糖残基C6原子来源于精氨酸而不是葡萄糖。
为了系统的提出米多霉素完整的生物合成途径,我们结合异源表达和系统突变,首先确定了米多霉素生物合成基因簇的左右两个边界分别位于orf-1-milA与milQ-orf+1之间,对其中包括的17个orf一一进行突变,除了milL突变没有影响之外,证明其它的16个基因与米多霉素的生物合成相关。
milG编码的是一个新颖的Radical SAM家族蛋白,它是唯一一个氧化还原酶候选基因,负责羟甲基胞嘧啶葡萄糖醛酸C4位上羟基氧化成羰基,在milG突变株的发酵液中,中间产物羟甲基胞嘧啶葡萄糖醛酸大量积累,这充分证明了其功能就是负责这一步关键的催化反应,这也是第一次在核苷类抗生素生物合成中报道的新型氧化酶基因。分别敲除两个氨基糖苷类磷酸转移酶基因milE和milQ,突变株都丧失了产生米多霉素的能力,推测这两个磷酸转移酶可能负责糖上的C2-C3间双键的形成。可能编码天冬氨酸/酪氨酸/芳香族氨基酸类氨基转移酶的milM和编码二氢吡啶甲酸合酶的milN基因的突变株均不能够再产生米多霉素,MilM可能参与催化精氨酸α位的氨基转化成羰基而形成α-酮酸,而MilN则负责α-羰基与脱羧后的己糖碳负离子之间的缩合。编码degT/dnrJ/eryC1/strS类氨基转移酶的milD和编码可能的连接酶功能的milH突变株都丧失了产生米多霉素的能力,推测前者是负责C4位上羰基的转氨反应,后者负责将激活的丝氨酸连接到C4位的氨基上,形成类似肽键的酰胺键。而中断LuxR家族的转录调节因子基因milO也消除了米多霉素的生产,说明它可能是一个途径专一性的调节基因。MilJ显示与Ubiquitone的羟甲基化酶有一定的同源性,可能负责精氨酸的gamma羟化;而MilI可能负责了丝氨酸的活化;ABC transporter基因milP的突变株也不产米多霉素,它很可能是米多霉素的抗性基因;编码Major Facilitator Superfamily的基因milk的突变株还能够产生米多霉素,但产量降低,它可能与磷酸葡萄糖的转运有关。
Mildiomycin (MIL) is a peptidyl nucleoside antibiotic with strong activity against powdery mildew disease of plants. In present work, the degenerate primers were designed based on blsM, the gene of CMP hydrolase in the blsticidin S biosynthetic gene cluster, together with its homologues. With the primers, six overlapping cosmids were screened from the genomic library of Streptoverticillum rimofaciens ZJU5119. 14A6, one of them can confer Streptomyces lividans 1326 to produce MIL, implying that it contains all the essential genes for biosynthesis of MIL.
The insertion sequence of 14A6 was determined and assembled into 43,561bp on which 41 ORFs were predicted by FramePlot beta4.0. The mutant of milA, a gene encoding CMP hydroxymethylase, could produce only dehydroxymethyl MIL (dHM-MIL), while neither of MIL and dHM-MIL can be biosynthesized when milB, homolog of blsM was disrupted. Recombinant MilA was purified in E. coli and shown to specifically introduce a C-5 hydroxymethyl group on CMP but not able to accept either cytosine or dCMP as substrate. The kinetic parameters of recombinant MilB showed that it hydrolyzed hydroxymethyl-CMP to hydroxymethyl-cytosine (HMC) more efficiently than did CMP to cytosine. With the CMP as substrate, the ratio of free HMC to cytosine generated by MilB and MilA was ca. 9:1 in in vitro assays while the ratio of MIL to dHM-MIL was 3:1 in the extracted broth of Streptoverticillum rimofaciens. The inconsistence was partly compensated by the substrate bias of MilC, which can catalyse the coupling of the cytosine or HMC with UDP-glucuronic acid into cytosylglucuronic acid (CGA) or HMCGA, respectively. The Kcat/Km of MilC to cytosine and HMC were 0.5250±0.0019 and 0.2719±0.0012, respectively.
A puzzling and interesting question regarding MIL biosynthesis was the origin of C-6 in carboxyl group. Using the stable isotope labeled L-arginine (U-13C6) to feed Streptoverticillum rimofaciens, the productivity of MIL with a mass of 520, 6 increments than that without isotope incorporation, increased to 11% from 2% after feeding of labeled L-arginine. Q-TOF/MS analyses of the purified mildiomycin indicated that all the fragments containing the guanidino-side chain gave a mass increment of 6, indicating thet all of six carbon atoms of labeled L-arginine were kept after the coupling of L-arginine or its derivative with glucuronic acid moiety, namely, C6 was derived from L-arginine rather than sugar as the precursors of MIL.
To propose the complete biosynthetic pathway of MIL, the boundaries were firstly determined via systamtic gene disruption as well as end sequencing of six overlapped cosmids. Two boundaries were located within orf-1-milA and milQ-orf+1. All included genes within the boundary were disrupted individually, and 16 genes were demonstrated to be involved in the biosynthesis of MIL except for milL, of which knock-out caused no effect on production of MIL.
The gene of milG encodes a unique Radical SAM family protein and is the only oxidase candidate supposed to be in charge of the oxidation of the hydroxyl group to carbonyl group in C4 of the hydroxymethyl cytosylglucuronic acid. In accordance with this assumption, intermediate of HMCGA was accumulated highly in the milG mutant, strongly supporting the role of MilG as a novel oxidase.in this key step. This was the first report of Radical SAM protein as the oxidase in the biosynthesis of nucleoside antibiotics.
Disruption of milE and milQ, two aminoglycoside phosphotransferase genes, abolished the production of MIL; they are presumably involved in the double bond formation between C2 and C3 of the sugar moiety. The gene of milM and milN, encoding an aspartate/tyrosine/aromatic aminotransferase and a dihydrodipicolinate synthetase respectively, were disrupted, and neither resultant mutant could produce MIL. MilM was supposed to convertα-amino group of L-arginine to carbonyl group, and MilN sequentially catalyze the coupling of the carbonyl group in theα-ketonic acid with the carboanion in the decarboxylated hexose. Another aminotransferase gene, namely milD, encoding a degT/dnrJ/eryC1/strS aminotransferase, was considered to transfer amino group to the carbonyl group in the C-4 of sugar residue. MilH, the homologue of BlsK, might be in charge of the attachment of activated L-serine to C4 group of sugar moiety to form amide-like bond in the MIL biosynthesis.
The disruption of a LuxR family regulator gene, milO, abolished the production of MIL, suggesting MilO should be a pathway-specific positive regulator. MilJ shows some homology with the Ubiquitone hydroxylase and postulated to be responsible for the hydroxylation ofγ-carbon in arginine residue. MilI was supposed to be involved in the activivation of L-serine. The mutant of an ABC transporter gene, milP, which was considered as the resistance gene, could not produce the MIL; the mutant of milk, a Major Facilitator Superfamily gene, produced less MIL compared to the wild type. MilK was proposed to be involved in the transportation of phosphogluconate.
引文
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