Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, Charlotte Auerbach Road, The King's Buildings, Edinburgh, EH9 3FL, United Kingdom.
School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London, E1 4NS, United Kingdom.
Phytochemistry. 2021 Dec;192:112953. doi: 10.1016/j.phytochem.2021.112953. Epub 2021 Sep 29.
Cyanobacteria are an ancient clade of photosynthetic prokaryotes, whose worldwide occurrence, especially in water, presents health hazards to humans and animals due to the production of a range of toxins (cyanotoxins). These include the sometimes co-occurring, non-encoded diaminoacid neurotoxins 2,4-diaminobutanoic acid (2,4-DAB) and its structural analogue β-N-methylaminoalanine (BMAA). Knowledge of the biosynthetic pathway for 2,4-DAB, and its role in cyanobacteria, is lacking. The aspartate 4-phosphate pathway is a known route of 2,4-DAB biosynthesis in other bacteria and in some plant species. Another pathway to 2,4-DAB has been described in Lathyrus species. Here, we use bioinformatics analyses to investigate hypotheses concerning 2,4-DAB biosynthesis in cyanobacteria. We assessed the presence or absence of each enzyme in candidate biosynthesis routes, the aspartate 4-phosphate pathway and a pathway to 2,4-DAB derived from S-adenosyl-L-methionine (SAM), in 130 cyanobacterial genomes using sequence alignment, profile hidden Markov models, substrate specificity/active site identification and the reconstruction of gene phylogenies. In the aspartate 4-phosphate pathway, for the 18 species encoding diaminobutanoate-2-oxo-glutarate transaminase, the co-localisation of genes encoding the transaminase with the downstream decarboxylase or ectoine synthase - often within hybrid non-ribosomal peptide synthetase (NRPS)-polyketide synthases (PKS) clusters, NRPS-independent siderophore (NIS) clusters and incomplete ectoine clusters - is compatible with the hypothesis that some cyanobacteria use the aspartate 4-phosphate pathway for 2,4-DAB production. Through this route, in cyanobacteria, 2,4-DAB may be functionally associated with environmental iron-scavenging, via the production of siderophores of the schizokinen/synechobactin type and of some polyamines. In the pathway to 2,4-DAB derived from SAM, eight cyanobacterial species encode homologs of SAM-dependent 3-amino-3-carboxypropyl transferases. Other enzymes in this pathway have not yet been purified or sequenced. Ultimately, the biosynthesis of 2,4-DAB appears to be either restricted to some cyanobacterial species, or there may be multiple and additional routes, and roles, for the synthesis of this neurotoxin.
蓝藻是光合原核生物的一个古老分支，由于其在世界范围内的存在，尤其是在水中，会产生一系列毒素（蓝藻毒素），对人类和动物的健康构成威胁。这些毒素包括有时共存的、非编码的二氨基丁酸神经毒素 2,4-二氨基丁酸（2,4-DAB）和其结构类似物β-N-甲基氨基丙氨酸（BMAA）。人们对 2,4-DAB 的生物合成途径及其在蓝藻中的作用知之甚少。天冬氨酸 4-磷酸途径是其他细菌和一些植物物种中 2,4-DAB 生物合成的已知途径。另一种途径已在野豌豆属物种中描述。在这里，我们使用生物信息学分析来研究蓝藻中 2,4-DAB 生物合成的假设。我们使用序列比对、轮廓隐马尔可夫模型、底物特异性/活性位点鉴定和基因系统发育重建，评估了候选生物合成途径中天冬氨酸 4-磷酸途径和源自 S-腺苷甲硫氨酸（SAM）的 2,4-DAB 途径中 130 个蓝藻基因组中每种酶的存在或缺失。对于 18 种编码二氨基丁酸-2-氧代戊二酸转氨酶的物种，编码转氨酶的基因与下游脱羧酶或章鱼碱合酶的共定位-通常在混合非核糖体肽合酶（NRPS）-聚酮合酶（PKS）簇、NRPS 独立铁载体（NIS）簇和不完整的章鱼碱簇内-与某些蓝藻使用天冬氨酸 4-磷酸途径生产 2,4-DAB 的假设是一致的。通过这种途径，在蓝藻中，2,4-DAB 可能通过产生节旋肽/章鱼碱型铁载体和一些多胺与环境中铁的清除有关。在源自 SAM 的 2,4-DAB 途径中，八种蓝藻物种编码 SAM 依赖性 3-氨基-3-羧基丙基转移酶的同源物。该途径中的其他酶尚未被纯化或测序。最终，2,4-DAB 的生物合成似乎要么仅限于某些蓝藻物种，要么可能有多种和额外的途径和作用来合成这种神经毒素。
