Prenylation（戊烯酰化）：從分子級别到臨床前景的全面解析

引言

Prenylation（戊烯酰化）是一種脂質修飾過程，涉及将戊烯基或異戊二烯基異戊二烯醇共價地連接配接到蛋白質的保守半胱氨酸殘基上。這個過程對許多蛋白質的正常功能至關重要，包括核層蛋白、真菌交配因子、Ras和Ras相關的GTP結合蛋白、蛋白激酶以及至少一種病毒蛋白。Prenylation（戊烯酰化）促進了大多數這些蛋白質與細胞膜的互相作用，這并不令人意外，因為涉及的脂質具有疏水性。此外，戊烯酰化似乎在涉及這些物種的幾種蛋白質互相作用中起着重要作用。本綜述主要關注戊烯蛋白質加工的酶學過程和戊烯酰化在細胞事件中的功能意義。

分子機制和功能影響

戊烯酰化是一個複雜的過程，涉及幾個酶促步驟。第一步是将異戊二烯基或戊烯基基團添加到目标蛋白質的半胱氨酸殘基上。然後通過蛋白酶的剪切作用去除蛋白質的末端氨基酸，暴露出戊烯酰化的半胱氨酸殘基。最後一步是向戊烯酰化的半胱氨酸殘基添加一個甲基基團。

戊烯酰化在許多蛋白質的正常功能中起着至關重要的作用。例如，Ras蛋白質的戊烯酰化對其正确定位到細胞質膜和激活下遊信号通路的能力至關重要。核層蛋白的戊烯酰化對核膜的正确組裝和核結構的維持非常重要。蛋白激酶的戊烯酰化對其正确定位到細胞質膜和與其他信号蛋白的互相作用非常重要。

發展和進展

近年來，在我們對蛋白質戊烯酰化的分子機制和功能後果的了解方面取得了重大進展。幾項研究已經确定了新的戊烯酰化蛋白質，并揭示了戊烯酰化在各種細胞過程中的作用。例如，已經發現戊烯酰化在自噬的調節中起到了一定作用，自噬是細胞降解和回收受損或不必要的細胞成分的過程。戊烯酰化也被證明在免疫反應調節和癌症發展中起到了作用。

應用

蛋白質戊烯酰化在細胞過程中的重要性促使開發了幾種針對戊烯酰化的藥物。例如，已經開發了戊烯酰轉移酶抑制劑（FTIs）作為潛在的抗癌治療藥物。這些藥物抑制戊烯酰轉移酶的活性，該酶對Ras蛋白質的戊烯酰化至關重要。通過抑制Ras蛋白質的戊烯酰化，FTIs阻止了促進細胞生長和增殖的下遊信号通路的激活。已經對幾種FTIs進行了臨床試驗，并且有些藥物在作為抗癌治療藥物方面顯示出了希望。

結論

總之，蛋白質戊烯酰化是一個複雜的過程，對許多蛋白質的正常功能起着至關重要的作用。最近的研究揭示了戊烯酰化的分子機制和功能後果，并确定了新的戊烯酰化蛋白質和戊烯酰化在細胞過程中的新角色。戊烯酰化在細胞過程中的重要性促使開發了幾種針對戊烯酰化的藥物，包括FTIs，這些藥物在作為抗癌治療藥物方面顯示出了希望。

Citations:

[1] Zhang, F. L., & Casey, P. J. (1996). Protein prenylation: molecular mechanisms and functional consequences. Annual review of biochemistry, 65(1), 241-269.https://www.scienceopen.com/document?vid=2c7a9717-9294-4adb-94ff-9b7b9b1d1a92

[2] https://en.wikipedia.org/wiki/Prenylation

## Introduction

Protein prenylation is a lipid modification process that involves the covalent attachment of either farnesyl or geranylgeranyl isoprenoids to conserved cysteine residues of proteins. This process is essential for the proper functioning of many proteins, including nuclear lamins, fungal mating factors, Ras and Ras-related GTP-binding proteins, protein kinases, and at least one viral protein. Prenylation promotes membrane interactions of most of these proteins, which is not surprising given the hydrophobicity of the lipids involved. In addition, prenylation appears to play a major role in several protein-protein interactions involving these species. The emphasis in this review is on the enzymology of prenyl protein processing and the functional significance of prenylation in cellular events.

## Molecular Mechanisms and Functional Consequences

Prenylation is a complex process that involves several enzymatic steps. The first step is the addition of an isoprenoid group to the cysteine residue of the target protein. This is followed by proteolytic cleavage of the terminal amino acids of the protein, which exposes the prenylated cysteine residue. The final step involves the addition of a methyl group to the prenylated cysteine residue.

Prenylation plays a crucial role in the proper functioning of many proteins. For example, prenylation of Ras proteins is essential for their proper localization to the plasma membrane and their ability to activate downstream signaling pathways. Prenylation of nuclear lamins is important for the proper assembly of the nuclear envelope and the maintenance of nuclear structure. Prenylation of protein kinases is important for their proper localization to the plasma membrane and their ability to interact with other signaling proteins.

## Development and Progress

In recent years, there has been significant progress in our understanding of the molecular mechanisms and functional consequences of protein prenylation. Several studies have identified new prenylated proteins and have shed light on the role of prenylation in various cellular processes. For example, prenylation has been shown to play a role in the regulation of autophagy, a process by which cells degrade and recycle damaged or unnecessary cellular components. Prenylation has also been shown to play a role in the regulation of the immune response and in the development of cancer.

## Applications

The importance of protein prenylation in cellular processes has led to the development of several drugs that target prenylation. For example, farnesyltransferase inhibitors (FTIs) have been developed as potential cancer therapeutics. These drugs inhibit the activity of farnesyltransferase, which is required for the prenylation of Ras proteins. By inhibiting Ras prenylation, FTIs prevent the activation of downstream signaling pathways that promote cell growth and proliferation. Several FTIs have been tested in clinical trials, and some have shown promise as cancer therapeutics.

## Conclusion

In conclusion, protein prenylation is a complex process that plays a crucial role in the proper functioning of many proteins. Recent studies have shed light on the molecular mechanisms and functional consequences of prenylation, and have identified new prenylated proteins and new roles for prenylation in cellular processes. The importance of prenylation in cellular processes has led to the development of several drugs that target prenylation, including FTIs, which have shown promise as cancer therapeutics.

Citations:

[1] https://www.scienceopen.com/document?vid=2c7a9717-9294-4adb-94ff-9b7b9b1d1a92

[2] https://pubmed.ncbi.nlm.nih.gov/8811180/

[3] https://www.sciencedirect.com/science/article/abs/pii/S1388198100000093

[4] https://www.annualreviews.org/doi/abs/10.1146/annurev.bi.65.070196.001325

[5] https://en.wikipedia.org/wiki/Prenylation

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