This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.


Sandbox GGC5

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Current revision (19:52, 28 April 2021) (edit) (undo)
 
(84 intermediate revisions not shown.)
Line 1: Line 1:
-
==p38 MAPK==
+
=='''Beta Lactamase'''==
-
<StructureSection load='1wfc' size='340' side='right' caption='p38 MAPK' scene=''78/781193/Colored_monomers/2>
+
<StructureSection load='3ZWF' size='340' side='right' caption='tRNAse Z Metallo-Beta Lactamase (homosapien)' scene=''>
-
== Function ==
+
Beta Lactamase is a highly conserved enzyme in both prokaryotes and eukaryotes. In prokaryotes, it gives bacteria such as ''E.coli'' antibiotic resistance. In eukaryotes, it acts as exo and endonucleases to regulate transcription activity.
-
MAPKs are '''M'''itogen '''A'''ctivated '''P'''rotein '''K'''inases. Kinases are proteins that participate in signaling pathways by phosphorylating molecules as a means of regulating their function (whether they are activated or not). Often these signals are a result of external stimuli. Mitogens are entities that trigger mitosis specifically. p38 MAPK is also referred to as a SAPK which stands for '''S'''tress '''A'''ctivated '''P'''rotein '''K'''inase. This is not surprisingly because p38 MAPK gets activated when cells are exposed to environmental stressors. Experiments in mice have shown that p38 MAPK is involved in the regulation of the cell cycle, apoptosis, cell differentiation, and senescence (cellular aging). There are four isoforms: α,β,δ, and γ.The molecule was discovered in the search for molecules that regulate Tumor Necrosis Factor production. All four of the isoforms have high specificity for their substrates. They are all found in different tissues, and can have opposing effects.
+
-
== Disease ==
+
=='''Background Information'''==
-
Much of the investigation into p38 MAPK has revolved around its role in inflammation, and cytokine production. Diseases where this protein plays are part include: Rheumatoid Arthritis, Crohn's Disease, Psoriasis, and Asthma. All four p38 MAPKs are implicated in RA. RA involves the attack of the synovium (joint lining) by immune cells.
+
There are several classes of antibiotics, including cephalosporin and penicillin <ref>doi: 10.1016/j.jmb.2019.04.002</ref>. Some common examples of specific drugs in these classes include cefazolin, cefadroxil, penicillin, ampicillin, and methicillin <ref>doi: 10.1016/j.jmb.2019.04.002</ref>. These antibiotics function by preventing bacteria from forming their cell wall, regardless if the bacteria are gram positive or gram negative <ref>doi: 10.1016/j.jmb.2019.04.002</ref>. These antibiotics all contain a beta-lactam ring <ref>https://doi.org/10.1021/cr030102i</ref>.
 +
Inside of the gram positive or gram negative bacteria, there is a protein called the penicillin binding protein. The penicillin binding proteins (PBPs) are what help the peptidoglycan walls to form by linking NAG and NAM chains together. The beta-lactam ring fits particularly well into the PBP, which is how antibiotics like penicillin prevent bacteria from synthesizing its cell wall.
-
Phosphorylated p38 MAPKs activate various substrates including: transcription factors, protein kinases, proteins in the cytosol & nucleus. This results in an inflammatory response, cell differentiation, cell-cycle arrest, apoptosis, cytokine production, and RNA splicing. p38 also plays a role in cell migration which is a feature of metastasis in cancerous cells. It also can inhibit cell growth through promoting apoptosis. Phosphatases control how long p38 MAPK is phosporylated, and the duration of phosphorylation corresponds to its affect. Longer phosphorylation corresponds to apoptosis, and shorter duration of phosphorylation corresponds to cell survival in response to growth factors.
+
[[Image:beta lactam ring in antibiotics.png]]
 +
Beta Lactam Ring present in Antibiotics
-
== Relevance ==
+
[[Image:Penicillin inhibition.svg]]
-
There is a lot of research going into the development of inhibitors of this enzyme. There are a few that are already known. Some very effective inhibitors are known as pyridinyl imidazole inhibitors because they resemble ATP, and are able to competitively inhibit the enzyme. ATP is normally bound at the active site to phosphorylate the molecule, and if it can't occupy that space the p38 MAPK never gets activated, and can't transmit inflammatory signals downstream.
+
Penicillin inhibition
 +
 
 +
=='''Mechanism of Antibiotic Beta Lactam Ring Resistance'''==
 +
Bacteria such as ''E. coli'' make and excrete an enzyme called beta lactamase <ref>DOI: 10.1080/10409230701279118</ref>. Bacteria can become resistant to antibiotics that contain lactam rings when the B-lactamase enzyme attacks the beta lactam ring (classified as a hydrolase). Once the beta lactam ring is sliced open, it is no longer functional <ref> DOI 10.2210/pdb3ZWF/pdb </ref>.
 +
 +
=='''Beta Lactamase in Humans (PDB: 3ZWF)'''==
 +
 
 +
In order to make mature tRNAs, first they have to be processed <ref>https://doi.org/10.1101/575373</ref>. The enzyme that does tRNA processing is called TRNase Z. In humans, the form of beta lactamase formed uses a zinc-dependent mechanism, noted as metallo-beta lactamase <ref>DOI: 10.1080/10409230701279118</ref>. These enzymes in humans function to regulate nuclear activity, providing exo and endonuclease activity.
 +
 
 +
=='''Structural highlights'''==
 +
 
 +
Macromolecules:
 +
Two chains (A,B) of Zinc phosphodiesterase ELAC Protein 1 <ref>DOI 10.2210/pdb3ZWF/pdb</ref>.
 +
 
 +
''Unique Ligands''
 +
 
 +
 
 +
- Phosphate (PO4) ligand on chains A and B of Zinc phosphodiesterase ELAC Protein 1 <ref>DOI 10.2210/pdb3ZWF/pdb</ref>.
 +
 
 +
<scene name='78/781193/Po4/1'>PO4 Ligand</scene>
 +
 
 +
- Zinc (Zn) ligand on chains A and B of Zinc phosphodiesterase ELAC Protein 1 <ref>DOI 10.2210/pdb3ZWF/pdb</ref>.
 +
 
 +
 
 +
<scene name='78/781193/2_zincs/1'>Zinc ions are adjacent to the phosphate to balance the charge</scene>
 +
 
 +
- 2007 hydrophobic amino acid residues <ref>DOI 10.2210/pdb3ZWF/pdb</ref>.
 +
<scene name='78/781193/Hydrophobic_amino_acids/1'>hydrophobic amino acid properties </scene>
 +
 
 +
- 1878 polar amino acid residues <ref>DOI 10.2210/pdb3ZWF/pdb</ref>.
 +
<scene name='78/781193/Polar_amino_acids/1'>polar amino acids</scene>
 +
 
 +
- Sodium (Na+) ion on chain B of Zinc phosphodiesterase ELAC Protein 1 <ref>DOI 10.2210/pdb3ZWF/pdb</ref>.
 +
<scene name='78/781193/Sodium_ion_enlarged/1'>Sodium Ion present</scene>
-
== Structural highlights ==
 
-
<scene name='78/781193/Colored_monomers/2'>Monomers</scene> and
 
-
<scene name='78/781193/P_binding_site/1'>ATP Binding Site</scene>
 
</StructureSection>
</StructureSection>
-
== References ==
 
-
1. Wilson, K.P.; Fitzgibbon, M.J.; Caron, P.R.; Griffith, J.P.; Chen, W.;
+
=='''Disease'''==
-
McCaffrey, P.G.; Chambers, S.P.; Su, M.S. Crystal Structure of p38 Mitogen-activated Protein Kinase. The Journal of Biological Chemistry. 1996, 271, 27696–27700.
+
If there are mutations in the tRNase Z metallo-beta lactamases, these enzymes have been implicated in several diseases including prostate cancer <ref>DOI: 10.1080/10409230701279118</ref>. While there is still much to learn about how these lactamases work inter-connectedly with other enzymes, research suggests that metallo-beta lactamases function as cleavage and polyadenylation factors <ref>https://doi.org/10.1101/575373</ref>.
 +
 
 +
 
 +
== '''Evolutionary Considerations''' ==
 +
 
 +
Beta Lactamase protein structure is highly conserved across both prokaryotes and eukaryotes <ref>doi: https://doi.org/10.1101/819797</ref>. Their presence indicates that these proteins are highly adaptable, with a wide range of substrates <ref>https://doi.org/10.1101/575373</ref>. The highly conserved nature of this structure suggests that the genetic material for beta lactamase is ancient in origin <ref>https://doi.org/10.1101/575373</ref>. They have found early beta lactamases in deep sea sediment, before the first antibiotic was ever encountered.
 +
 
-
2. Zarubin, T.; Han, J. Activation and signaling of the p38 MAP kinase pathway. Cell Research. 2005, 15, 11-18.
+
== '''References''' ==
 +
<references/>
-
3. Li, Y.; Sassano, A.; Majchrzak, B.; Deb, D.K.; Levy, D.E.; Gaestel, M.; Nebreda, A.R.; Fish, E.N.; Platanias, L.C. Role of p38α Map Kinase in Type I Interferon Signaling. The Journal of Biological Chemistry. 2004, 279, 970-979.
+
[1]
 +
[2]
 +
[3]
 +
[4]
 +
[5]
 +
[6]
 +
[7]
 +
[8]

Current revision

Contents

Beta Lactamase

tRNAse Z Metallo-Beta Lactamase (homosapien)

Drag the structure with the mouse to rotate

Disease

If there are mutations in the tRNase Z metallo-beta lactamases, these enzymes have been implicated in several diseases including prostate cancer [15]. While there is still much to learn about how these lactamases work inter-connectedly with other enzymes, research suggests that metallo-beta lactamases function as cleavage and polyadenylation factors [16].


Evolutionary Considerations

Beta Lactamase protein structure is highly conserved across both prokaryotes and eukaryotes [17]. Their presence indicates that these proteins are highly adaptable, with a wide range of substrates [18]. The highly conserved nature of this structure suggests that the genetic material for beta lactamase is ancient in origin [19]. They have found early beta lactamases in deep sea sediment, before the first antibiotic was ever encountered.


References

  1. ↑ Tooke CL, Hinchliffe P, Bragginton EC, Colenso CK, Hirvonen VHA, Takebayashi Y, Spencer J. beta-Lactamases and beta-Lactamase Inhibitors in the 21st Century. J Mol Biol. 2019 Aug 23;431(18):3472-3500. doi: 10.1016/j.jmb.2019.04.002. Epub, 2019 Apr 5. PMID:30959050 doi:http://dx.doi.org/10.1016/j.jmb.2019.04.002
  2. ↑ Tooke CL, Hinchliffe P, Bragginton EC, Colenso CK, Hirvonen VHA, Takebayashi Y, Spencer J. beta-Lactamases and beta-Lactamase Inhibitors in the 21st Century. J Mol Biol. 2019 Aug 23;431(18):3472-3500. doi: 10.1016/j.jmb.2019.04.002. Epub, 2019 Apr 5. PMID:30959050 doi:http://dx.doi.org/10.1016/j.jmb.2019.04.002
  3. ↑ Tooke CL, Hinchliffe P, Bragginton EC, Colenso CK, Hirvonen VHA, Takebayashi Y, Spencer J. beta-Lactamases and beta-Lactamase Inhibitors in the 21st Century. J Mol Biol. 2019 Aug 23;431(18):3472-3500. doi: 10.1016/j.jmb.2019.04.002. Epub, 2019 Apr 5. PMID:30959050 doi:http://dx.doi.org/10.1016/j.jmb.2019.04.002
  4. ↑ https://doi.org/10.1021/cr030102i
  5. ↑ Dominski Z. Nucleases of the metallo-beta-lactamase family and their role in DNA and RNA metabolism. Crit Rev Biochem Mol Biol. 2007 Mar-Apr;42(2):67-93. doi:, 10.1080/10409230701279118. PMID:17453916 doi:http://dx.doi.org/10.1080/10409230701279118
  6. ↑ doi: https://dx.doi.org/10.2210/pdb3ZWF/pdb
  7. ↑ https://doi.org/10.1101/575373
  8. ↑ Dominski Z. Nucleases of the metallo-beta-lactamase family and their role in DNA and RNA metabolism. Crit Rev Biochem Mol Biol. 2007 Mar-Apr;42(2):67-93. doi:, 10.1080/10409230701279118. PMID:17453916 doi:http://dx.doi.org/10.1080/10409230701279118
  9. ↑ doi: https://dx.doi.org/10.2210/pdb3ZWF/pdb
  10. ↑ doi: https://dx.doi.org/10.2210/pdb3ZWF/pdb
  11. ↑ doi: https://dx.doi.org/10.2210/pdb3ZWF/pdb
  12. ↑ doi: https://dx.doi.org/10.2210/pdb3ZWF/pdb
  13. ↑ doi: https://dx.doi.org/10.2210/pdb3ZWF/pdb
  14. ↑ doi: https://dx.doi.org/10.2210/pdb3ZWF/pdb
  15. ↑ Dominski Z. Nucleases of the metallo-beta-lactamase family and their role in DNA and RNA metabolism. Crit Rev Biochem Mol Biol. 2007 Mar-Apr;42(2):67-93. doi:, 10.1080/10409230701279118. PMID:17453916 doi:http://dx.doi.org/10.1080/10409230701279118
  16. ↑ https://doi.org/10.1101/575373
  17. ↑ doi: https://dx.doi.org/https
  18. ↑ https://doi.org/10.1101/575373
  19. ↑ https://doi.org/10.1101/575373

[1] [2] [3] [4] [5] [6] [7] [8]

Retrieved from "http://52.214.119.220/wiki/index.php/Sandbox_GGC5"
Personal tools