WBR0935

Author	PageAuthor::William J Gibson (Reviewed by Serge Korjian)
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Biochemistry
Sub Category	SubCategory::Hematology, SubCategory::General Principles
Prompt	[[Prompt::Lenalidomide is a highly effective chemotherapeutic agent against multiple myeloma. A scientist is investigating the anti-neoplatic mechanism of lenalidomide. She finds that addition of lenalidomide to multiple myeloma cells decreases the protein abundance of the plasma cell essential transcription factors IKZF1 and IKZF3. She finds that lenalidomide binds to the CRBN-CRL4 complex, which then induces a post-translational modification of IKZF1 and IKZF3. Which of the following enzymatic activities does CRBN-CRL4 most likely possess?]]
Answer A	AnswerA::Glycosyltransferase
Answer A Explanation	[[AnswerAExp::Glycosylation refers to the addition of a carbohydrate to a protein. The glycosylation of proteins does not target them for degradation. Glycosylation is often necessary for the proper function or folding of the modified protein. One example of a heavily glycosylated protein family is the heparin sulfate proteoglycans.]]
Answer B	AnswerB::Farnesyltransferase
Answer B Explanation	AnswerBExp::Farnesyl groups can be added to proteins for their proper localization to cell membranes. Farnesylation does not target proteins for degradation.
Answer C	AnswerC::Gamma-carboxylase
Answer C Explanation	AnswerCExp::Vitamin K is gamma-carboxylated for its normal function.
Answer D	AnswerD::Hydroxylase
Answer D Explanation	AnswerDExp::Hydroxylation refers to the addition of an –OH group to a compound. Hydroxylation is an important step in the synthesis of steroid compounds. Proline hydroxylation is accomplished with Vitamin C as a cofactor in the synthesis of collagen.
Answer E	AnswerE::Ubiquitin ligase
Answer E Explanation	AnswerEExp::Proteins can be targeted for degradation by the addition of ubiquitin molecules to lysine residues.
Right Answer	RightAnswer::E
Explanation	[[Explanation::Upon addition of lenalidomide, two transcription factors are post-translationally modified and their abundance is shown to decrease i.e. they are most likely degraded. The post-translational modification that induces degradation of proteins is polyubiquitination. Ubiquitination is a process whereby ubiquitin is attached to a substrate protein leading to several downstream effects. Polyubiquitination, or the addition of multiple ubiquitin molecules in a chain to a certain protein, targets the protein for degradation by the proteasome, an enzymatic complex that breaks down unneeded proteins via proteolysis. It is important to note that not every addition of a ubiquitin molecule to a protein tags the latter for degradation, this process only occurs with polyubiquitination. Ubiquitination requires three main enzymes ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3). The process is demonstrated below. Educational Objective: Proteins can be targeted for degradation by the addition of ubiquitin molecules to lysine residues. References: Lu G, Middleton RE, Sun H, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science. 2014;343(6168):305-9. Image Atrribution: Roger B. Dodd]]
Approved	Approved::Yes
Keyword	WBRKeyword::Ubiquitin, WBRKeyword::Post-translational modification, WBRKeyword::Protein, WBRKeyword::Translation, WBRKeyword::Molecular biology, WBRKeyword::Cell
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