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Ubiquitination and Disease

Q: In what kind of diseases play defects in ubiquitination an essential role?

- Cancer : different forms (lung cancer, lymphomas, carcinomas, colon cancer, Fanconi-anaemia related cancers) - Neurodegenerative diseases: e.g. Parkinson's, Alzheimer's and Huntington's - Viral diseases : e.g. HIV, HPV, en Herpes virus

Q: How can E2 be inhibited?

- Block E2 loading by blocking E1-E2 interaction - Block E2-dependent UBL transfer using allosteric effectors or inhibitors of E2 catalytic activity, So, either block the exchange of E1 by E2 or block the ubiquitin transfer to the substrate.

Q: Which types of E3 ligases are there and how do they differ?

- RING : most E3 ligases * The ubiquitin is never coupled to RING, directly transferred from E2 to target protein. - HECT : 2 subdomains, one with active site Cys in the C-lobe and one with E2 binding site in N-lobe. Substrate binding via domains located outside HECT domain. * Ubiquitin first goes to the Cys after which it binds to the target protein (so extra step).

Q: How is Mdm2 (RING E3) associates with disease and how can it be treated?

- Mdm2 (RING E3) binds and ubiquitinates the tumorsuppressor protein p53 --> p53 us degraded by the proteasome --> lost tumor supression (highly expressed in some tumors, duplicated locus). - P53 : transcription factor and important tumorsuppresor, stimulates apoptosis, inhibits cell cycle and stimulates repair of DNA damage - MDM2-p53 interaction can be inhibited by Nutlins (Nutley inhibitor) ; they bind to MDM2 which prevents p53 binding.

12 important questions on Ubiquitination and Disease

In what kind of diseases play defects in ubiquitination an essential role?

- Cancer: different forms (lung cancer, lymphomas, carcinomas, colon cancer, Fanconi-anaemia related cancers)
- Neurodegenerative diseases: e.g. Parkinson's, Alzheimer's and Huntington's
- Viral diseases: e.g. HIV, HPV, en Herpes virus

How does the ubiquitination cascade go?

1. Activation of E1 via acyl-adenylate intermediate
2. E1 binds to ubiquitin in the place of AMP
3. E1 gets exchanged for E2
4a. E3 binds to the E2-ubiquitin complex
4b. E3 and E2 dissociate, Ubiquitin is linked to target protein
5. Degradation/regulation

* E1= Ub-activating enzyme
* E2= Ub-conjugating enzyme
* E3= Ub ligase

What are UBLs (ubiquitin-like proteins)?

UBLs have similar enzyme cascades to ubiquitin, but different functions.

- Functions Ub: breakdown, cell cycle, transcription regulation
- Functions Ubls: Activation cullin-E3s, breakdown, cell cycle, transcription regulation, anti-viral, autophagy, anti-oxidant regulation, tRNA modification.

How can E1 be inhibited?

- By mechanism-based inhibitors
- Inhibit the activation via acyl-adenylate intermediate.

* Bind UBL
* Covalent modification

How can E2 be inhibited?

- Block E2 loading by blocking E1-E2 interaction
- Block E2-dependent UBL transfer using allosteric effectors or inhibitors of E2 catalytic activity,

So, either block the exchange of E1 by E2 or block the ubiquitin transfer to the substrate.

Which types of E3 ligases are there and how do they differ?

- RING: most E3 ligases
* The ubiquitin is never coupled to RING, directly transferred from E2 to target protein.

- HECT: 2 subdomains, one with active site Cys in the C-lobe and one with E2 binding site in N-lobe. Substrate binding via domains located outside HECT domain.
* Ubiquitin first goes to the Cys after which it binds to the target protein (so extra step).

What are possible ways to inhibit E3 ligase?

- Disrupt interaction between E3 and substrate
- Disrupt interaction between E2 and E3
- Inhibit/block catalysis

How is Mdm2 (RING E3) associates with disease and how can it be treated?

- Mdm2 (RING E3) binds and ubiquitinates the tumorsuppressor protein p53 --> p53 us degraded by the proteasome --> lost tumor supression (highly expressed in some tumors, duplicated locus).

- P53: transcription factor and important tumorsuppresor, stimulates apoptosis, inhibits cell cycle and stimulates repair of DNA damage

- MDM2-p53 interaction can be inhibited by Nutlins (Nutley inhibitor); they bind to MDM2 which prevents p53 binding.

What are the types of deubiquitinating enzymes (DUBs) and their function?

- Cysteine protease and Zn-metalloprotease
- Remove ubiquitin from substrate

Why is the modification of proteins by ubiquitination much more complex and more diverse than protein phosphorylation?

There are more enzymes in the ubiquitination cascade and more variation because of the various ubiquitin chains. There are more E3 ligases than kinases. There are multiple enzymes involved (pyramid like structure). There are different combinations of E2 and E3 possible. Almost every protein in the human body is ubiquitinated.

* There are >8 different polyUb chains

Why does Bortezomib not treat other types of cancer?

Because of its ADME (Absorption, Distribution, Metabolism, Excretion). In multiple myeloma the white blood cells are the target compartment. The distribution of Bortezomib is more favorable for white blood cells.

* Irreversible inhibitors, rapidly reversible inhibitors etc. Will have different tissue distribution as compared to the slowly reversible bortezombin and therefore may show proteasome inhibition in different tumor types

How specific is the inhibition of the ubiquitin cascade? And inhibition Proteasomes? And Dubs?

- Inhibitor ligases: low specificity higher in the cascade (E1) and high specificity lower in the cascade (E3) because E3 has substrate-specificity. Intermediate specificity for E2.
- Inhibitor Proteasome: low specificity. It's ate the end of the cascade and it inhibits the degradation of all proteins which are K-48 linked.
- Inhibitor DUBs: has intermediate specificity. There are many molecules which receive a certain chain.

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Medical Biochemistry and Pathophysiology

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Ubiquitination and Disease

12 important questions on Ubiquitination and Disease

In what kind of diseases play defects in ubiquitination an essential role?

How does the ubiquitination cascade go?

What are UBLs (ubiquitin-like proteins)?

How can E1 be inhibited?

How can E2 be inhibited?

Which types of E3 ligases are there and how do they differ?

What are possible ways to inhibit E3 ligase?

How is Mdm2 (RING E3) associates with disease and how can it be treated?

What are the types of deubiquitinating enzymes (DUBs) and their function?

Why is the modification of proteins by ubiquitination much more complex and more diverse than protein phosphorylation?

Why does Bortezomib not treat other types of cancer?

How specific is the inhibition of the ubiquitin cascade? And inhibition Proteasomes? And Dubs?

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