在希塔基米辛生物合成中的多基基酸合成后修饰机制
Fumitaka Kudo1, Kazuma Tsuboi1, Mutsumi Ikezaki1
1Department of Chemistry, Tokyo Institute of Technology, 2-12-1 Meguro-ku, O-okayama, Tokyo, 152-8551, Japan.
Chembiochem : a European journal of chemical biology
|June 7, 2024
概括
研究人员阐明了 hitachimycin 生物合成的后聚基酸合成酶 (PKS) 修饰途径. 基因失活揭示了一个关键的中间体,并确定了参与制造这种双循环麦克罗拉克坦抗生素的酶.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 自然产品生物合成 自然产品生物合成
背景情况:
- 希塔奇米辛是一种含有 (S) -β-氨 (β-Phe) 的双循环麦克罗拉克坦抗生素.
- 虽然涉及β-氨基酸和多基合成酶 (PKSs) 的初始步骤已被理解,但形成 hitachimycin 独特结构的 PKS 后修改是未知的.
研究的目的:
- 为了研究 hitachimycin 生物合成中 PKS 后的修饰机制.
- 确定负责构建双循环结构的特定基因和酶.
主要方法:
- 在Streptomyces scabrisporus中,六个假定PKS后修饰基因 (hitM1-hitM6) 的非激活.
- 对基因淘汰菌株中累积的中间体的分析.
- 采用纯化的酶和中间体进行体外酶分析.
主要成果:
- 删除hitM4导致积累了一种全-trans-2,4,6,8,18-pentaene麦克罗拉克坦,被确定为PKS后的早期中间体.
- 删除hitM1的结果是10-O-甲基甲基-10-oxohitachimycin (M1-A). 这样就能得到10-O-甲基甲基-10-oxohitachimycin (M1-A).
- 酶性研究表明,HitM1 (一种减少酶) 和HitM6 (一种甲基转移酶) 对于将M1-A转化为 hitachimycin至关重要.
结论:
- 已经提出了一种可信的PKS后修改途径,用于 hitachimycin 生合成.
- HitM4参与了早期阶段,而HitM1和HitM6催化了后来的修饰,包括还原和甲基化,以形成最终的抗生素结构.
相关概念视频
01:19Allosteric Proteins-ATCase
5.7K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.7K
02:04Covalently Linked Protein Regulators
6.8K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
These groups modify specific amino acids in a protein....
6.8K
02:36Transfer RNA Synthesis
11.9K
One of the unique features of tRNA is the presence of modified bases. In some tRNAs, modified bases account for nearly 20% of the total bases in the molecule. Altogether, these unusual bases protect the tRNA from enzymatic degradation by RNases.
Each of these chemical modifications is carried by a specific enzyme, post-transcription. All of these enzymes have unique base and site-specificity. Methylation, the most common chemical modification, is carried by at least nine different enzymes, with...
Each of these chemical modifications is carried by a specific enzyme, post-transcription. All of these enzymes have unique base and site-specificity. Methylation, the most common chemical modification, is carried by at least nine different enzymes, with...
11.9K
01:12Cycloaddition Reactions: MO Requirements for Photochemical Activation
2.1K
Some cycloaddition reactions are activated by heat, while others are initiated by light. For example, a [2 + 2] cycloaddition between two ethylene molecules occurs only in the presence of light. It is photochemically allowed but thermally forbidden.
2.1K
01:24Phase II Reactions: Acetylation Reactions
216
Acetylation, a phase II biotransformation reaction, introduces an acetyl group to drugs or their metabolites. Acetyltransferase enzymes facilitate this reaction, which resembles α-amino acid conjugation due to the addition of a functional group to the drug molecule.
The substrates for acetylation are typically drugs or their metabolites with an amino, sulfonamide, or hydrazine functional group. Acetylation can occur at several points in the drug molecule, including primary, secondary, and...
The substrates for acetylation are typically drugs or their metabolites with an amino, sulfonamide, or hydrazine functional group. Acetylation can occur at several points in the drug molecule, including primary, secondary, and...
216
01:17Phase II Reactions: Methylation Reactions
177
Methylation is a phase II biotransformation process involving the attachment of a methyl group to a substrate. Enzymes known as methyltransferases orchestrate this reaction.
The mechanism of methylation unfolds in two stages. The first stage sees a methyltransferase enzyme facilitating the transfer of a methyl group from S-adenosylmethionine (SAM) to the substrate, forming S-adenosylhomocysteine (SAH). The second stage involves further metabolism of SAH into homocysteine, which can be recycled...
The mechanism of methylation unfolds in two stages. The first stage sees a methyltransferase enzyme facilitating the transfer of a methyl group from S-adenosylmethionine (SAM) to the substrate, forming S-adenosylhomocysteine (SAH). The second stage involves further metabolism of SAH into homocysteine, which can be recycled...
177