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| - | =Apolipoprotein A-I= | + | ==HIV-1 Protease== |
| - | ==Structure==
| + | An infection of the Human Immuno-deficiency Virus can cause Acquired Immunodeficiency Syndrome (AIDS). HIV attacks the CD4 T cells that are an essential part of the cell-mediated immune response, without which the immune system cannot fight against other infections or cancers, causing AIDS. There are currently 37 million people worldwide living with HIV/AIDS, with approximately 1 million new cases each year along with approximately 1 million deaths a year. |
| - | <StructureSection load='1av1' size='340' side='right' caption='Apolipoprotein A-I' scene=''>
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| - | Apolipoproteins are proteins that coat lipoprotein surface that binds lipids such as cholesterol, low-density lipoprotein (LDL), or high-density lipoproteins (HDL) in lipid metabolism. They function in the transport of such lipids in their structure that acts as a ligand to cell receptors and lipid transport proteins. <ref> Voet, D., Voet, J. G., & Pratt, C. W. (2016). Fundamentals of Biochemistry (5th ed.). Hoboken, NJ: John Wiley & Sons.</ref> They are important in the binding and transportation of lipids throughout the body, necessary in energy structural components, and nutrients.
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| - | Apolipoprotein A-I is a protein of APOA1 gene located on the 11th chromosome found in humans that is a component of HDL. Gene for APOA1 protein contains a total of 4 exons that is synthesized for the protein, used in lipid metabolism of HDL. <ref> APOA1 gene: MedlinePlus Genetics. (2020, August 18). Retrieved October 26, 2020, from https://medlineplus.gov/genetics/gene/apoa1/</ref>
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| - | Apolipoprotein a-1 (apoA-I) is a fairly small molecule that consists of a total of 243 residues and is 29-kD polypeptide in size. Structure in <scene name='75/752268/Color/10'>color</scene> is shown in rainbow, in arrangement from N-terminus (red) of amine group to C-terminus (dark blue) end of carboxyl group.
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| - | == Function ==
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| - | Apolipoprotein A-I is responsible in the reverse transport of cholesterol to the liver. It contains amphipathic structure sequences of helices in its repeating <scene name='75/752268/Polar/1'> polar </scene>hydrophilic and non-polar hydrophobic groups that form helices are what allows the interaction between hydrophobic properties of water, such as in the blood stream and hydrophobic lipids.
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| - | Apolipoprotein A-I is a protein APOA1 gene in humans that is a component of HDL, which a form of good cholesterol in human's diet, used in the transport of cholesterol and phospholipids in the body through the bloodstream in the reverse transport of cholesterol from the tissues to the liver of hepatocytes. They promote cholesterol efflux, a pathway in transferring intracellular cholesterol to extracellular acceptors, from tissues and act as a cofactor for the lecithin cholesterol acyltransferase (LCAT).<ref>Yano, K., Ohkawa, R., Sato, M., Yoshimoto, A., Ichimura, N., Kameda, T., . . . Tozuka, M. (2016, November 09). Cholesterol Efflux Capacity of Apolipoprotein A-I Varies with the Extent of Differentiation and Foam Cell Formation of THP-1 Cells. Retrieved November 14, 2020, from https://www.hindawi.com/journals/jl/2016/9891316/</ref>
| + | Antiretroviral Therapy is one of the HIV treatments that is most effective as the combinations of different medicines reduce the viral load to become undetectable and non-transmissible and also allows the immune system to recuperate and increase the CD4 count. Protease Inhibitors are one of the FDA approved medicines that target the viral Aspartyl Protease to prevent the HIV from making more copies of itself. |
| - | == Clinical significance ==
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| - | Apolipoprotein A-1 is found to be as an indicator for cardiovascular disease and atherosclerotic cardiovascular disease. Since APOA1 is a component of HDL associated with good form of cholesterol, when ABOAB (apolipoprotein B) a component of LDL, a form of bad cholesterol levels are elevated in blood can signal as a risk factor for development in hardening of arterial walls and blockage. <ref> Test ID: APOAB Apolipoprotein A1 and B, Serum. (n.d.). Retrieved November 14, 2020, from Test ID: APOAB Apolipoprotein A1 and B, Serum. (n.d.). Retrieved November 14, 2020, from Test ID: APOAB Apolipoprotein A1 and B, Serum</ref> High-density lipoprotein complex is important in the clearing of fats through absorption of cholesterol that is transported into the liver where it is synthesized into bile salts or excreted.<ref> LDL & HDL: Good & Bad Cholesterol. (2020, January 31). Retrieved November 14, 2020, from https://www.cdc.gov/cholesterol/ldl_hdl.htm</ref><ref>Cohen, D. (2008, April). Balancing cholesterol synthesis and absorption in the gastrointestinal tract. Retrieved November 14, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2390860/</ref>
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| - | '''Apolipoprotein A-I (Milano)''' is a mutant form of apolipoprotein A-I associated in reducing coronary artery disease to those genetically predisposition. <ref>CR;, C. (n.d.). Apolipoprotein A-I(Milano): Current perspectives. Retrieved November 14, 2020, from https://pubmed.ncbi.nlm.nih.gov/12642784/</ref> Mutation Milano was first discovered in from a patient in Limone sul Garda, Northern Italy or alarming elevated triglycerides and low HDL with no signs of atherosclerosis or cardiovascular disease. Mutation occurs at 173 residue of <scene name='75/752268/Milano/1'>arginine</scene> replaced with cysteine. <ref>Lowe, D. (2016, November 16). The Long Saga of Apo-A1 Milano. Retrieved November 14, 2020, from https://blogs.sciencemag.org/pipeline/archives/2016/11/16/the-long-saga-of-apo-a1-milano</ref> | + | <StructureSection load='3VEV' size='340' side='right' caption='Caption for this structure' scene=''> |
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| - | == Diseases == | |
| - | '''Tangier disease''' | |
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| - | Genetic disorder with significantly reduced HDL in the blood caused by mutation of APOA1 gene (ABCA1) caused by abnormal pre-mRNA spicing, in the loss of 22 amino acids of premature stop codon.<ref>Maranghi, M., Truglio, G., Gallo, A., Grieco, E., Verrienti, A., Montali, A., . . . Lucarelli, M. (2018, November 30). A novel splicing mutation in the ABCA1 gene, causing Tangier disease and familial HDL deficiency in a large family. Retrieved November 14, 2020, from https://www.sciencedirect.com/science/article/pii/S0006291X18324781</ref> As a result of decreased apolipoprotein A-1 synthesized, cells undergo large lipid fluxes and accumulated cholesterol and fats. Accumulation of cholesterol in cell due to lack of transport is toxic and impairs cell function. Visible signs of the disease include yellow-orange tonsils and formation of foam cells of lipid-laden macrophages.<ref>McConnell, J. (2019, January 17). Tangier Disease. Retrieved November 15, 2020, from https://www.cancertherapyadvisor.com/home/decision-support-in-medicine/labmed/tangier-disease/</ref>
| + | == Function == |
| - | | + | HIV-1 Aspartyl Proteases are homo-dimeric proteolytic enzymes, also known as endopeptidases that allow water molecules to act as nucleophiles during catalysis when activated by 2 aspartic acid residues that make up the <scene name='75/752268/Active_site_without_inhibitor/1'>active site</scene>. Usually, the active site consists of a triad (ASP-THR-GLY) on each monomer with the catalytic residue being D25. |
| - | '''Amyloidosis'''
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| - | Rare disease caused from abnormal protein amyloid is built up in areas of the heart, kidneys, liver, and other organs. Amyloid, not normally found in the body, is produced from mutation of APOA1 gene that can be caused by 13 of 50 known variants of apolipoprotein A-1 gene between residues 50 to 93 and 170 to 178. Three of mutations are known to cause gene variations that lead to two different frameshifts at amino acids asparagine and alanine (p.Asn74fs and p.Ala154fs) and single amino acid exchange (p.Leu170Pro). <ref>Eriksson, M., Schönland, S., Yumlu, S., Hegenbart, U., Von Hutten, H., Gioeva, Z., . . . Röcken, C. (2009, May). Hereditary apolipoprotein AI-associated amyloidosis in surgical pathology specimens: Identification of three novel mutations in the APOA1 gene. Retrieved November 15, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671344/</ref>
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| - | Symptoms of amyloidosis is not evident until disease is more progressed. Range of symptoms are also dependent on organ(s) effected that include swelling in legs and ankles, enlarged tongue, shortness of breath, and/or skin conditions such as patches from easily bruising. <ref>Amyloidosis. (2020, March 14). Retrieved November 15, 2020, from https://www.mayoclinic.org/diseases-conditions/amyloidosis/symptoms-causes/syc-20353178</ref>
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| - | '''Alzheimer’s'''
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| | + | Aspartyl Protease cleaves the Gag and Gag-Pol polyproteins that encode for other structural proteins and enzymes crucial for viral maturation. Hence, HIV-1 Protease Inhibitors have been developed to inhibit the viral protease enzyme to prevent the production and release of mature, infectious HIV virions. Here is how an inhibitor binds to the protease to form a <scene name='75/752268/Hiv-1_protease-inhibitor/1'>HIV-1 protease-inhibitor complex</scene>. |
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| | + | == Disease == |
| | + | Protease inhibitors along with reverse transcriptase inhibitors have been proven to be effective in reducing the viral load to slow the development of AIDS, however in recent years, mutations on the HIV-1 Protease have become a new challenge for researchers and pharmaceutical companies. Here is an image of a <scene name='75/752268/Mdr_protease_18_mutation/1'>multi-drug resistant HIV-1 Protease enzyme</scene> from a patient for whom the protease inhibitor regimen is no longer effective. The HIV-1 strain from this patient has 9 mutations per monomer. The ineffectiveness of the protease inhibitors can allow the viral load to increase and allow the progression of AIDS. |
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| | + | == Relevance == |
| | + | Once again, if the structure of the protease enzyme changes due to mutations, the protease inhibitors will not be effective in preventing viral maturation. The relevance of these mutations can be seen in the active site expansion that takes place, especially at <scene name='75/752268/Mutations_v82a_and_i84v/1'>residue positions 82 and 84</scene>, among others. Here, it can be seen that the V82A and the I84V mutation causes the distance between the active site flap to become wider as the amino acid side chains become shorter. The change in the distance of amino acid 83,84,182 and 184 is approximately 1.5 A each in amino acid residues according to Logsdon et al, 2004.This conformational change reduces the binding affinity of the protease inhibitor to the active site. |
| | | | |
| | == Structural highlights == | | == Structural highlights == |
| | + | Other notable structural highlights include the 1. <scene name='75/752268/Inhibitor_binding_site_of_mut1/1'>Inhibitor Binding Site of Mutated HIV-1 Protease</scene>, |
| | + | 2. <scene name='75/752268/Active_site_flap/1'>Active Site Flap of Mutated HIV-1 Protease</scene>, |
| | + | 3. <scene name='75/752268/Alpha-d-glucose/1'>Interaction with Alpha-D-glucose</scene>, and |
| | + | 4. <scene name='75/752268/Catalytic_residue_shift/1'>Catalytic Residue Shift |
| | + | </scene> |
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| - | Apolipoprotein a-1 (apoA-I) is a fairly small molecule that consists of a total of 243 residues and is 29-kD polypeptide in size. Its structure consists of two helical domains that include a four-helix of antiparallel bundle by N terminal and two helix bundle at the C terminal end. ApoA-I consists of <scene name='75/752268/Chains/1'>four chains</scene> alpha helices including chain A (orange), B (blue), C (red), and D (green) as displayed, in which an infinity like structure. C terminal domain of carboxyl group is known to participate in role in lipid binding for transport, found following between residues <scene name='75/752268/Cterm_binding/1'>(190-243).</scene> At the central region, two antiparallel helices form a flexible domain of connected bundles of each end of helices.<ref>And, X. (2011, November 04). Crystal Structure of C-terminal Truncated Apolipoprotein A-I Reveals the Assembly of High Density Lipoprotein (HDL) by Dimerization. Retrieved November 14, 2020, from https://www.jbc.org/content/286/44/38570.abstract?sid=eee11503-e692-438c-a298-52d329852b25</ref> | |
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| - | Apolipoprotein a-1 in the monomer form <scene name='75/752268/Truncated/4'>truncated</scene> (lacking 1-43 residues) consists of unique pseudo-continuous alpha helix highlighted by kinks at <scene name='75/752268/Truncated/3'>Pro residues</scene>, spaced approximately every 22 residues.<ref>Nagao, K., Hata, M., Tanaka, K., Takechi, Y., Nguyen, D., Dhanasekaran, P., . . . Saito, H. (2014, January). The roles of C-terminal helices of human apolipoprotein A-I in formation of high-density lipoprotein particles. Retrieved November 14, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863607/</ref> | |
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| - | Biomarkers of coronary artery disease are also found to be of modification at glutamate residue 243 of truncated APOA1 of single amino acid. | |
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| | </StructureSection> | | </StructureSection> |
| | == References == | | == References == |
| - | 1. Voet, D., Voet, J. G., & Pratt, C. W. (2016). Fundamentals of Biochemistry (5th ed.). Hoboken, NJ: John Wiley & Sons.<references/>
| + | Logsdon BC, Vickrey JF, Martin P, Proteasa G, Koepke JI, Terlecky SR, Wawrzak Z, Winters MA, Merigan TC, Kovari LC. Crystal structures of a multidrug-resistant human immunodeficiency virus type 1 protease reveal an expanded active-site cavity. J Virol. 2004 Mar;78(6):3123-32. doi: 10.1128/jvi.78.6.3123-3132.2004. PMID: 14990731; PMCID: PMC354404. |
| - | | + | <references/> |
| - | 2. APOA1 gene: MedlinePlus Genetics. (2020, August 18). Retrieved October 26, 2020, from https://medlineplus.gov/genetics/gene/apoa1/<references/>
| + | Munshi S, Chen Z, Li Y, Olsen DB, Fraley ME, Hungate RW, Kuo LC. Rapid X-ray diffraction analysis of HIV-1 protease-inhibitor complexes: inhibitor exchange in single crystals of the bound enzyme. Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):1053-60. doi: 10.1107/s0907444998003588. PMID: 9757136. |
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| - | 3. Mangaraj, M., Nanda, R., & Panda, S. (2016, July). Apolipoprotein A-I: A Molecule of Diverse Function. Retrieved November 04, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910842<references/>
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| - | 4. Yano, K., Ohkawa, R., Sato, M., Yoshimoto, A., Ichimura, N., Kameda, T., . . . Tozuka, M. (2016, November 09). Cholesterol Efflux Capacity of Apolipoprotein A-I Varies with the Extent of Differentiation and Foam Cell Formation of THP-1 Cells. Retrieved November 14, 2020, from https://www.hindawi.com/journals/jl/2016/9891316/<references/>
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| - | 5. Test ID: APOAB Apolipoprotein A1 and B, Serum. (n.d.). Retrieved November 14, 2020, from Test ID: APOAB Apolipoprotein A1 and B, Serum. (n.d.). Retrieved November 14, 2020, from Test ID: APOAB Apolipoprotein A1 and B, Serum<references/>
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| - | 6. LDL & HDL: Good & Bad Cholesterol. (2020, January 31). Retrieved November 14, 2020, from https://www.cdc.gov/cholesterol/ldl_hdl.htm<references/> | + | |
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| - | 7. Cohen, D. (2008, April). Balancing cholesterol synthesis and absorption in the gastrointestinal tract. Retrieved November 14, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2390860/<references/>
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| - | 8. CR;, C. (n.d.). Apolipoprotein A-I(Milano): Current perspectives. Retrieved November 14, 2020, from https://pubmed.ncbi.nlm.nih.gov/12642784/<references/>
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| - | 9. Lowe, D. (2016, November 16). The Long Saga of Apo-A1 Milano. Retrieved November 14, 2020, from https://blogs.sciencemag.org/pipeline/archives/2016/11/16/the-long-saga-of-apo-a1-milano <references/>
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| - | 10. Nagao, K., Hata, M., Tanaka, K., Takechi, Y., Nguyen, D., Dhanasekaran, P., . . . Saito, H. (2014, January). The roles of C-terminal helices of human apolipoprotein A-I in formation of high-density lipoprotein particles. Retrieved November 14, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863607/<references/>
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| - | 11. And, X. (2011, November 04). Crystal Structure of C-terminal Truncated Apolipoprotein A-I Reveals the Assembly of High Density Lipoprotein (HDL) by Dimerization. Retrieved November 14, 2020, from https://www.jbc.org/content/286/44/38570.abstract?sid=eee11503-e692-438c-a298-52d329852b25<references/>
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| - | 12. Maranghi, M., Truglio, G., Gallo, A., Grieco, E., Verrienti, A., Montali, A., . . . Lucarelli, M. (2018, November 30). A novel splicing mutation in the ABCA1 gene, causing Tangier disease and familial HDL deficiency in a large family. Retrieved November 14, 2020, from https://www.sciencedirect.com/science/article/pii/S0006291X18324781<references/>
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| - | | + | |
| - | 13. McConnell, J. (2019, January 17). Tangier Disease. Retrieved November 15, 2020, from https://www.cancertherapyadvisor.com/home/decision-support-in-medicine/labmed/tangier-disease/<references/>
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| - | | + | |
| - | 14. Eriksson, M., Schönland, S., Yumlu, S., Hegenbart, U., Von Hutten, H., Gioeva, Z., . . . Röcken, C. (2009, May). Hereditary apolipoprotein AI-associated amyloidosis in surgical pathology specimens: Identification of three novel mutations in the APOA1 gene. Retrieved November 15, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671344/<references/>
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| - | | + | |
| - | 15.Amyloidosis. (2020, March 14). Retrieved November 15, 2020, from https://www.mayoclinic.org/diseases-conditions/amyloidosis/symptoms-causes/syc-20353178<references/>
| + | |
An infection of the Human Immuno-deficiency Virus can cause Acquired Immunodeficiency Syndrome (AIDS). HIV attacks the CD4 T cells that are an essential part of the cell-mediated immune response, without which the immune system cannot fight against other infections or cancers, causing AIDS. There are currently 37 million people worldwide living with HIV/AIDS, with approximately 1 million new cases each year along with approximately 1 million deaths a year.
Antiretroviral Therapy is one of the HIV treatments that is most effective as the combinations of different medicines reduce the viral load to become undetectable and non-transmissible and also allows the immune system to recuperate and increase the CD4 count. Protease Inhibitors are one of the FDA approved medicines that target the viral Aspartyl Protease to prevent the HIV from making more copies of itself.
Logsdon BC, Vickrey JF, Martin P, Proteasa G, Koepke JI, Terlecky SR, Wawrzak Z, Winters MA, Merigan TC, Kovari LC. Crystal structures of a multidrug-resistant human immunodeficiency virus type 1 protease reveal an expanded active-site cavity. J Virol. 2004 Mar;78(6):3123-32. doi: 10.1128/jvi.78.6.3123-3132.2004. PMID: 14990731; PMCID: PMC354404.
Munshi S, Chen Z, Li Y, Olsen DB, Fraley ME, Hungate RW, Kuo LC. Rapid X-ray diffraction analysis of HIV-1 protease-inhibitor complexes: inhibitor exchange in single crystals of the bound enzyme. Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):1053-60. doi: 10.1107/s0907444998003588. PMID: 9757136.
