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==5YPI Mechanism of NDM-1==
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==GAPDH (Glyceraldehyde-3-Phosphate Dehydrogenase)==
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<StructureSection load='5YPI' size='340' side='right' caption='Caption for this structure' scene='/78/781194/5ypi-1/1'>
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The 5YPI structure of NDM-1 contains 14,682 atoms, 14,184 bonds, 2729 groups, and 8 chains.
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New Delhi metallo-beta-lactamases (NDMs), pose a serious threat due to their extremely efficient mechanism of hydrolysis on beta-lactam antibiotics. These antibiotics target the penicillin-binding proteins in enzymes found anchored in the cell membrane, which are involved in the cross-linking of the bacterial cell wall. The beta-lactam ring binds to different penicillin-binding proteins making them unable to do cell wall synthesis which leads to death of the bacterial cell. The NDM-1 gene causes the bacterium to produce an enzyme that neutralizes even the strongest antibiotic family: (Carbapenems)and only used as last resort. The bacteria strain that carries the NDM-1 gene are so dangerous because we have very few ways to fight them. Metallo-beta-lactamases-mediated hydrolysis happens in two steps: cleavage of the amide bond and protonation of the generated intermediate .After the formation of a Michaels complex (ES), a water/hydroxide molecule residing between the two Zn(II) ions acts as a nucleophile to attack the carbonyl carbon (C7) and cleave the C–N bond next the intermediate is protonated, and an EP complex is tentatively formed before product is release from the enzyme pocket, this was first detected in a Klebsiella pneumoniae case in India (hence the name)in 2009.My paper" The mechanism of NDM-1-catalyzed carbapenem hydrolysis is distinct from that of penicillin or cephalosporin hydrolysis" explores the mechanism reaction of New Delhi metallo-beta-lactamases using NMR and crystallography, the hydrolysis of three enzyme-intermediates are examined, EI1, EI2, and EP, The data suggested that the hydrolytic intermediates are protonated by a bulky water molecule incoming from the β-face. This research is important because it could help provide a design model for mechanism-based inhibitors.
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The mechanism of NDM-1-catalyzed carbapenem hydrolysis is distinct from that of penicillin or cephalosporin hydrolysis
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<StructureSection load='3VEV' size='340' side='right' caption='GAPDH' scene=''>
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Han Feng, Xuehui Liu, Sheng Wang, Joy Fleming, Da-Cheng Wang & Wei Liu
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== Function == Hydrolase
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GAPDH is a protein known as Glyceraldehyde-3-Phosphate dehydrogenase. This protein is also known as the "housekeeping" protein of the cell, it consists of an average of 335 amino acids, and it is considered a heme. It is also considered a catalyst to break down glucose to create energy and to form carbon molecules. It has many functions in the cell and is considered very important.<ref>PMID: 16474839</ref> <ref>PMID: 17573533; PMCID: PMC1904167</ref> This protein is mostly expressed in the most vital organs, the liver, brain, kidneys, and heart.
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== Disease == New Delhi metallo-beta-lactamase 1 is an enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics.
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== Structural highlights ==
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<scene name='78/781194/Secondary_structure/2'>Secondary Structure</scene> This scene shows the different secondary structures color-coded.
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<scene name='78/781194/Secondary_structure_2/1'>secondary structure 2</scene>
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{{Template:ColorKey_Helix}},
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{{Template:ColorKey_Strand}},
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{{Template:ColorKey_Loop}},
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{{Template:ColorKey_Turn}}.
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<scene name='78/781194/Composition/1'>Composition</scene> This scene shows the Protein, solvent, and ligand sites color coded below.
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== Function ==
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{{Template:ColorKey Composition Protein}}
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{{Template:ColorKey Composition Ligand}}
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{{Template:ColorKey Composition Solvent}}
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<scene name='78/781194/Elements/1'>Elements</scene> This scene shows the different elements color coded.
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This Particular Protein Plays a big role in Glycolysis and activities in the nucleus. Glyceraldehyde-3-phosphate dehydrogenase is a very important enzyme that catalyzes the first step of the glycolysis pathway.<ref>PMID: 11205159</ref> This is done by converting D-glyceraldehyde-3-phosphate to 3-phospho-D glyceroyl phosphate. The catalytic reaction begins with the reactants of D-glyceraldehyde-3-phosphate, NAD+, and phosphate. This reaction then proceeds with the products of (2R)-3- phospho-D glyceroyl phosphate, H ion, and NADH. This reaction then proceeds in the glycolysis pathway and creates pyruvate from D-glyceraldehyde-3-phosphate.<ref>PMID: 11205159</ref>
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{{Template:ColorKey_Element_C}}
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{{Template:ColorKey_Element_H}}
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{{Template:ColorKey_Element_O}}
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{{Template:ColorKey_Element_N}}
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{{Template:ColorKey_Element_P}}
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{{Template:ColorKey_Element_S}}
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{{Template:ColorKey_Element_Se}}
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{{Template:ColorKey_Element_Fe}}
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<scene name='78/781194/8chains/2'>Chains</scene> This scene shows the 8 chains linked together.
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Glyceraldehyde-3-Phosphate dehydrogenase has a big role in the nucleus.<ref>PMID: 16474839</ref> <ref>PMID: 17573533; PMCID: PMC1904167</ref>It is a part of many processes such as DNA replication, transcription, RNA transport, and apoptosis. Although it participates in all of those nuclear activities, it is mostly known to initiate apoptosis and transcription of the genes that are known to be involved in the antiapoptotic pathways and cell proliferation. GAPDH also plays a role in regulating of telomere length. Many biochemists have determined that this protein interacts with some types of DNA damages. Examples of them are apurinic/ apyrimidinic sites, nucleotide analogs, and covalent DNA adducts with alkylating agents. This then indicates and confirms that it participates in DNA repair by interacting with repair proteins such as APE1.<ref>PMID: 16474839</ref>
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<scene name='78/781194/Zn_pairs/1'>Zn Pairs</scene> This scene shows the 8 Zn pairs(one for each chain).
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This protein also plays a part in carbohydrate degradation. It catalyzes an energy-yielding step in carbohydrate metabolism. This happens when the nicotinamide adenine dinucleotide and the inorganic phosphate are present.<ref>PMID: 17573533; PMCID: PMC1904167</ref> This protein is a tetramer of chains that are identical.<ref>PMID: 11205159</ref>
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<scene name='78/781194/5ypi_elements_only/1'>elements-only</scene> This scene shows a view of the molecules without the secondary structures.
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== Regulation ==
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Glyceraldehyde-3-Phosphate dehydrogenase is regulated by being inhibited by Fumarate through the formation of S-(2-succinyl) cysteine residues.<ref>PMID: 17573533; PMCID: PMC1904167</ref> <ref>PMID: 11205159</ref>
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== Disease ==
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GAPDH is expressed in many diseases and disorders. The main diseases and disorders that were confirmed from the expression of GAPDH are cancers and neurodegeneration. It has been confirmed that GAPDH is expressed in many cancers as its antiapoptotic function protects the tumor and cancerous cells in the body. The protection of those cells promotes tumorigeneses and their proliferation.<ref>PMID: 16474839</ref> <ref>PMID: 17573533; PMCID: PMC1904167</ref>GAPDH also protects against the shortening of telomeres. The shortening of telomeres is caused by chemotherapy. Furthermore, Oxidative Stress impairs protein function. By impairing GAPDH, it will cause the aging and the apoptosis of the cell. GAPDH can also manage to induce the biological aging of the cells which have been proved to maintain tumor growth and production.
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</StructureSection>
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When paired with the right protein, GAPDH can be expressed in neurodegenerative diseases. The protein interaction with GAPDH can affect it functions such as energy metabolism, apoptosis, DNA replication, tRNA transport, and DNA repair. When the function of this Protein is affected, it could lead to disorders such as Parkinson’s disease and Huntington’s disease.<ref>PMID: 16474839</ref> <ref>PMID: 17573533; PMCID: PMC1904167</ref>
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== Relevance ==
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This protein is a component in many reactions and helps the eukaryote function in many ways at the cellular level. If affected by protein interactions, it will have a big impact on the eukaryote especially in the vital organs of the animal or human as it plays a big role in the vital organs. <ref>PMID: 11205159</ref> It will also lose its function and can be fatal to the human body as its important functions are disturbed and disrupted.
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== Structural highlights ==
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<scene name='78/781194/Interaction_with_r-proteins/1'>protein interaction functional site</scene> This protein interacts with another protein that detects degradation by AVR genes, while <scene name='78/781194/Disulfide_bridge/1'>Disulfide Bridge interactions with SO4</scene> is an interaction of sulfide ions. Furthurmore, <scene name='78/781194/Ndp2_interaction/1'>NDP2 Interaction</scene> is the Nucleoside-Diphosphate Kinase. When bound it is inhibited. Not only does this protein interact with chemicals and R-proteins, but it also has <scene name='78/781194/Q_protein_interactions/1'>Q-Protein Interactions</scene> this is mostly involved in the nuclease when transcription takes place.
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</StructureSection>
== References ==
== References ==
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1. Tatton WG, Chalmers-Redman RM, Elstner M, Leesch W, Jagodzinski FB, Stupak DP, Sugrue MM, Tatton NA. Glyceraldehyde-3-phosphate dehydrogenase in neurodegeneration and apoptosis signaling. J Neural Transm Suppl. 2000;(60):77-100. doi: 10.1007/978-3-7091-6301-6_5. PMID: 11205159.
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2. Carujo S, Estanyol JM, Ejarque A, Agell N, Bachs O, Pujol MJ. Glyceraldehyde 3-phosphate dehydrogenase is a SET-binding protein and regulates cyclin B-cdk1 activity. Oncogene. 2006 Jul 6;25(29):4033-42. doi: 10.1038/sj.onc.1209433. Epub 2006 Feb 13. PMID: 16474839.
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3. Kosova, A.A., Khodyreva, S.N. & Lavrik, O.I. Role of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in DNA repair. Biochemistry Moscow 82, 643–654 (2017). https://doi.org/10.1134/S0006297917060013
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4. Fermani S, Sparla F, Falini G, Martelli PL, Casadio R, Pupillo P, Ripamonti A, Trost P. Molecular mechanism of thioredoxin regulation in photosynthetic A2B2-glyceraldehyde-3-phosphate dehydrogenase. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11109-14. doi: 10.1073/pnas.0611636104. Epub 2007 Jun 15. PMID: 17573533; PMCID: PMC1904167.
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<references/>
<references/>
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https://www.nature.com/articles/s41467-017-02339-w
 
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https://rdcu.be/MgiZ
 

Current revision

GAPDH (Glyceraldehyde-3-Phosphate Dehydrogenase)

GAPDH

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References

1. Tatton WG, Chalmers-Redman RM, Elstner M, Leesch W, Jagodzinski FB, Stupak DP, Sugrue MM, Tatton NA. Glyceraldehyde-3-phosphate dehydrogenase in neurodegeneration and apoptosis signaling. J Neural Transm Suppl. 2000;(60):77-100. doi: 10.1007/978-3-7091-6301-6_5. PMID: 11205159.

2. Carujo S, Estanyol JM, Ejarque A, Agell N, Bachs O, Pujol MJ. Glyceraldehyde 3-phosphate dehydrogenase is a SET-binding protein and regulates cyclin B-cdk1 activity. Oncogene. 2006 Jul 6;25(29):4033-42. doi: 10.1038/sj.onc.1209433. Epub 2006 Feb 13. PMID: 16474839.

3. Kosova, A.A., Khodyreva, S.N. & Lavrik, O.I. Role of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in DNA repair. Biochemistry Moscow 82, 643–654 (2017). https://doi.org/10.1134/S0006297917060013

4. Fermani S, Sparla F, Falini G, Martelli PL, Casadio R, Pupillo P, Ripamonti A, Trost P. Molecular mechanism of thioredoxin regulation in photosynthetic A2B2-glyceraldehyde-3-phosphate dehydrogenase. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11109-14. doi: 10.1073/pnas.0611636104. Epub 2007 Jun 15. PMID: 17573533; PMCID: PMC1904167.

  1. Carujo S, Estanyol JM, Ejarque A, Agell N, Bachs O, Pujol MJ. Glyceraldehyde 3-phosphate dehydrogenase is a SET-binding protein and regulates cyclin B-cdk1 activity. Oncogene. 2006 Jul 6;25(29):4033-42. doi: 10.1038/sj.onc.1209433. Epub 2006 Feb, 13. PMID:16474839 doi:http://dx.doi.org/10.1038/sj.onc.1209433
  2. PMID: 17573533; PMCID: PMC1904167
  3. Tatton WG, Chalmers-Redman RM, Elstner M, Leesch W, Jagodzinski FB, Stupak DP, Sugrue MM, Tatton NA. Glyceraldehyde-3-phosphate dehydrogenase in neurodegeneration and apoptosis signaling. J Neural Transm Suppl. 2000;(60):77-100. doi: 10.1007/978-3-7091-6301-6_5. PMID:11205159 doi:http://dx.doi.org/10.1007/978-3-7091-6301-6_5
  4. Tatton WG, Chalmers-Redman RM, Elstner M, Leesch W, Jagodzinski FB, Stupak DP, Sugrue MM, Tatton NA. Glyceraldehyde-3-phosphate dehydrogenase in neurodegeneration and apoptosis signaling. J Neural Transm Suppl. 2000;(60):77-100. doi: 10.1007/978-3-7091-6301-6_5. PMID:11205159 doi:http://dx.doi.org/10.1007/978-3-7091-6301-6_5
  5. Carujo S, Estanyol JM, Ejarque A, Agell N, Bachs O, Pujol MJ. Glyceraldehyde 3-phosphate dehydrogenase is a SET-binding protein and regulates cyclin B-cdk1 activity. Oncogene. 2006 Jul 6;25(29):4033-42. doi: 10.1038/sj.onc.1209433. Epub 2006 Feb, 13. PMID:16474839 doi:http://dx.doi.org/10.1038/sj.onc.1209433
  6. PMID: 17573533; PMCID: PMC1904167
  7. Carujo S, Estanyol JM, Ejarque A, Agell N, Bachs O, Pujol MJ. Glyceraldehyde 3-phosphate dehydrogenase is a SET-binding protein and regulates cyclin B-cdk1 activity. Oncogene. 2006 Jul 6;25(29):4033-42. doi: 10.1038/sj.onc.1209433. Epub 2006 Feb, 13. PMID:16474839 doi:http://dx.doi.org/10.1038/sj.onc.1209433
  8. PMID: 17573533; PMCID: PMC1904167
  9. Tatton WG, Chalmers-Redman RM, Elstner M, Leesch W, Jagodzinski FB, Stupak DP, Sugrue MM, Tatton NA. Glyceraldehyde-3-phosphate dehydrogenase in neurodegeneration and apoptosis signaling. J Neural Transm Suppl. 2000;(60):77-100. doi: 10.1007/978-3-7091-6301-6_5. PMID:11205159 doi:http://dx.doi.org/10.1007/978-3-7091-6301-6_5
  10. PMID: 17573533; PMCID: PMC1904167
  11. Tatton WG, Chalmers-Redman RM, Elstner M, Leesch W, Jagodzinski FB, Stupak DP, Sugrue MM, Tatton NA. Glyceraldehyde-3-phosphate dehydrogenase in neurodegeneration and apoptosis signaling. J Neural Transm Suppl. 2000;(60):77-100. doi: 10.1007/978-3-7091-6301-6_5. PMID:11205159 doi:http://dx.doi.org/10.1007/978-3-7091-6301-6_5
  12. Carujo S, Estanyol JM, Ejarque A, Agell N, Bachs O, Pujol MJ. Glyceraldehyde 3-phosphate dehydrogenase is a SET-binding protein and regulates cyclin B-cdk1 activity. Oncogene. 2006 Jul 6;25(29):4033-42. doi: 10.1038/sj.onc.1209433. Epub 2006 Feb, 13. PMID:16474839 doi:http://dx.doi.org/10.1038/sj.onc.1209433
  13. PMID: 17573533; PMCID: PMC1904167
  14. Carujo S, Estanyol JM, Ejarque A, Agell N, Bachs O, Pujol MJ. Glyceraldehyde 3-phosphate dehydrogenase is a SET-binding protein and regulates cyclin B-cdk1 activity. Oncogene. 2006 Jul 6;25(29):4033-42. doi: 10.1038/sj.onc.1209433. Epub 2006 Feb, 13. PMID:16474839 doi:http://dx.doi.org/10.1038/sj.onc.1209433
  15. PMID: 17573533; PMCID: PMC1904167
  16. Tatton WG, Chalmers-Redman RM, Elstner M, Leesch W, Jagodzinski FB, Stupak DP, Sugrue MM, Tatton NA. Glyceraldehyde-3-phosphate dehydrogenase in neurodegeneration and apoptosis signaling. J Neural Transm Suppl. 2000;(60):77-100. doi: 10.1007/978-3-7091-6301-6_5. PMID:11205159 doi:http://dx.doi.org/10.1007/978-3-7091-6301-6_5
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