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UPSC MainsMEDICAL-SCIENCE-PAPER-I202210 Marks
Q8.

Explain the process of initiation of protein synthesis in eukaryotes. Enumerate any four inhibitors of protein synthesis with their mechanism of action.

How to Approach

This question requires a detailed understanding of the eukaryotic protein synthesis initiation process and knowledge of common protein synthesis inhibitors. The answer should begin by outlining the key steps of initiation – including cap recognition, ribosome recruitment, and scanning. Subsequently, it should enumerate four inhibitors, detailing their specific target and mechanism of action. A structured approach, utilizing headings and bullet points, will enhance clarity and readability. Focus on biochemical details and avoid overly simplistic explanations.

Model Answer

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Introduction

Protein synthesis, a fundamental process in all living organisms, is the creation of proteins from RNA templates. In eukaryotes, this process is significantly more complex than in prokaryotes, involving a multitude of initiation factors and regulatory mechanisms. The initiation phase is particularly crucial, as it determines the fidelity and efficiency of translation. Errors in initiation can lead to the production of non-functional proteins or even trigger cellular stress responses. Understanding the intricacies of eukaryotic initiation is vital for comprehending gene expression and developing targeted therapies for various diseases. This answer will detail the process of initiation and explore several inhibitors that disrupt this essential pathway.

Eukaryotic Protein Synthesis Initiation

Eukaryotic protein synthesis initiation is a multi-step process that can be broadly divided into the following stages:

1. Cap Recognition and eIF4F Complex Formation

  • The process begins with the binding of the eukaryotic initiation factor 4E (eIF4E) to the 7-methylguanosine cap (m7G cap) present at the 5' end of the mRNA.
  • eIF4E recruits other initiation factors, including eIF4G and eIF4A, forming the eIF4F complex.
  • eIF4A is an RNA helicase that unwinds secondary structures in the 5' untranslated region (UTR) of the mRNA, facilitating ribosome scanning.
  • eIF4B enhances the helicase activity of eIF4A.

2. Ribosome Recruitment

  • The 40S ribosomal subunit, in complex with eIF1 and eIF1A, is recruited to the eIF4F complex.
  • eIF3, a large multi-subunit complex, binds to the 40S subunit, preventing premature association with the 60S subunit.
  • This 40S pre-initiation complex then scans the mRNA in a 5' to 3' direction.

3. Scanning and Start Codon Recognition

  • The 40S subunit scans the mRNA for the start codon, AUG.
  • Kozak consensus sequence (GCCRCCAUGG) surrounding the AUG codon enhances translation initiation efficiency.
  • Once the AUG codon is identified, eIF1 dissociates, and eIF5 promotes GTP hydrolysis by eIF2.

4. 60S Subunit Joining and Initiation Complex Formation

  • GTP hydrolysis by eIF2 triggers conformational changes that allow eIF5B to deliver the 60S ribosomal subunit.
  • The 60S subunit joins the 40S subunit, forming the complete 80S initiation complex.
  • eIFs are released, and the ribosome is now ready to begin elongation.

Inhibitors of Protein Synthesis

Several compounds can inhibit protein synthesis at various stages. Here are four examples:

Inhibitor Mechanism of Action Stage of Inhibition
Cycloheximide Binds to the large (60S) ribosomal subunit, blocking translocation of peptidyl-tRNA. Elongation (but can also affect initiation)
Puromycin Mimics tRNA and binds to the A-site of the ribosome, causing premature chain termination. Elongation/Termination
Streptomycin Binds to the 30S ribosomal subunit, causing misreading of mRNA and inhibiting initiation. Initiation/Elongation
Chloramphenicol Binds to the 50S ribosomal subunit, inhibiting peptidyl transferase activity. Elongation

Conclusion

The initiation of protein synthesis in eukaryotes is a highly regulated and complex process, essential for cellular function. Disruptions in this process, whether through genetic mutations or pharmacological interventions, can have profound consequences. Understanding the intricate steps involved and the mechanisms of action of protein synthesis inhibitors is crucial for developing novel therapeutic strategies targeting diseases like cancer and infectious diseases. Further research into the regulatory networks governing initiation will undoubtedly reveal new avenues for therapeutic intervention and a deeper understanding of gene expression.

Answer Length

This is a comprehensive model answer for learning purposes and may exceed the word limit. In the exam, always adhere to the prescribed word count.

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Additional Resources

Key Definitions

eIF4F
eIF4F is a protein complex crucial for initiating translation in eukaryotes. It consists of eIF4E (cap-binding protein), eIF4G (scaffolding protein), and eIF4A (RNA helicase). It facilitates ribosome recruitment to the mRNA.
Kozak Sequence
The Kozak sequence (GCCRCCAUGG) is a consensus sequence found around the start codon (AUG) in eukaryotic mRNAs. It enhances the efficiency of ribosome binding and initiation of translation.

Key Statistics

Approximately 80% of human genes are regulated at the level of translation initiation (estimated as of 2010, based on studies of translational control mechanisms).

Source: Lodish H, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000.

It is estimated that approximately 5-10% of human diseases are caused by defects in protein synthesis or folding (based on data from the National Institutes of Health as of 2015).

Source: National Institutes of Health (NIH)

Examples

Viral Manipulation of Initiation

Many viruses, such as poliovirus, hijack the host cell's translational machinery by utilizing internal ribosome entry sites (IRES) instead of relying on the cap-dependent initiation pathway. This allows them to efficiently translate their viral proteins even when host cell cap-dependent translation is suppressed.

Frequently Asked Questions

▶What is the role of GTP in initiation?

GTP hydrolysis by eIF2 is a critical regulatory step in initiation. It triggers conformational changes in the initiation factors, allowing for the recruitment of the 60S ribosomal subunit and the formation of the functional 80S ribosome. It acts as a molecular switch, committing the ribosome to translation.

Topics Covered

BiochemistryMolecular BiologyTranslationRibosomesGenetic Code
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