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23 results on '"Manthei, Kelly A."'

5. Rescue of Familial Lecithin:Cholesterol Acyltranferase Deficiency Mutations with an Allosteric Activator

Author

Manthei, Kelly A., Tremonti, Grace E., Chang, Louise, Niemela¨, Akseli, Giorgi, Laura, Koivuniemi, Artturi, and Tesmer, John Joseph Grubb

Abstract

Lecithin:cholesterol acyltransferase (LCAT) deficiencies represent severe disorders characterized by aberrant cholesterol esterification in plasma, leading to life-threatening conditions. This study investigates the efficacy of Compound 2, a piperidinyl pyrazolopyridine allosteric activator that binds the membrane-binding domain of LCAT, in rescuing the activity of LCAT variants associated with disease. The variants K218N, N228K, and G230R, all located in the cap and lid domains of LCAT, demonstrated notable activity restoration in response to Compound 2. Molecular dynamics simulations and structural modeling indicate that these mutations disrupt the lid and membrane binding domain, with Compound 2 potentially dampening these structural alterations. Conversely, variants such as M252K and F382V in the cap and α/β-hydrolase domain, respectively, exhibited limited or no rescue by Compound 2. Future research should prioritize in vivo investigations that would validate the therapeutic potential of Compound 2 and related activators in familial LCAT deficiency patients with mutations in the cap and lid of the enzyme.SIGNIFICANCE STATEMENTLecithin:cholesterol acyltranferase (LCAT) catalyzes the first step of reverse cholesterol transport, namely the esterification of cholesterol in high density lipoprotein particles. Somatic mutations in LCAT lead to excess cholesterol in blood plasma and, in severe cases, kidney failure. In this study, we show that recently discovered small molecule activators can rescue function in LCAT-deficient variants when the mutations occur in the lid and cap domains of the enzyme.

Published
2024
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9. Lecithin:cholesterol acyltransferase: symposium on 50 years of biomedical research from its discovery to latest findings

Author

Norum, Kaare R., primary, Remaley, Alan T., additional, Miettinen, Helena E., additional, Strøm, Erik H., additional, Balbo, Bruno E.P., additional, Sampaio, Carlos A.T.L., additional, Wiig, Ingrid, additional, Kuivenhoven, Jan Albert, additional, Calabresi, Laura, additional, Tesmer, John J., additional, Zhou, Mingyue, additional, Ng, Dominic S., additional, Skeie, Bjørn, additional, Karathanasis, Sotirios K., additional, Manthei, Kelly A., additional, and Retterstøl, Kjetil, additional

Published
2020
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11. Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol

Author

Manthei, Kelly A, primary, Yang, Shyh-Ming, additional, Baljinnyam, Bolormaa, additional, Chang, Louise, additional, Glukhova, Alisa, additional, Yuan, Wenmin, additional, Freeman, Lita A, additional, Maloney, David J, additional, Schwendeman, Anna, additional, Remaley, Alan T, additional, Jadhav, Ajit, additional, and Tesmer, John JG, additional

Published
2018
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12. Author response: Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol

Author

Manthei, Kelly A, primary, Yang, Shyh-Ming, additional, Baljinnyam, Bolormaa, additional, Chang, Louise, additional, Glukhova, Alisa, additional, Yuan, Wenmin, additional, Freeman, Lita A, additional, Maloney, David J, additional, Schwendeman, Anna, additional, Remaley, Alan T, additional, Jadhav, Ajit, additional, and Tesmer, John JG, additional

Published
2018
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13. Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol

Author

Manthei, Kelly A., primary, Yang, Shyh-Ming, additional, Baljinnyam, Bolormaa, additional, Chang, Louise, additional, Glukhova, Alisa, additional, Yuan, Wenmin, additional, Freeman, Lita A., additional, Maloney, David J., additional, Schwendeman, Anna, additional, Remaley, Alan T., additional, Jadhav, Ajit, additional, and Tesmer, John J.G., additional

Published
2018
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16. A retractable lid in lecithin:cholesterol acyltransferase provides a structural mechanism for activation by apolipoprotein A-I

Author

Manthei, Kelly A., primary, Ahn, Joomi, additional, Glukhova, Alisa, additional, Yuan, Wenmin, additional, Larkin, Christopher, additional, Manett, Taylor D., additional, Chang, Louise, additional, Shayman, James A., additional, Axley, Milton J., additional, Schwendeman, Anna, additional, and Tesmer, John J.G., additional

Published
2017
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17. Lecithin:Cholesterol Acyltransferase Activation by Sulfhydryl-Reactive Small Molecules: Role of Cysteine-31

Author

Freeman, Lita A., primary, Demosky, Stephen J., additional, Konaklieva, Monika, additional, Kuskovsky, Rostislav, additional, Aponte, Angel, additional, Ossoli, Alice F., additional, Gordon, Scott M., additional, Koby, Ross F., additional, Manthei, Kelly A., additional, Shen, Min, additional, Vaisman, Boris L., additional, Shamburek, Robert D., additional, Jadhav, Ajit, additional, Calabresi, Laura, additional, Gucek, Marjan, additional, Tesmer, John J.G., additional, Levine, Rodney L., additional, and Remaley, Alan T., additional

Published
2017
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22. Structural and biochemical characterization of the mitomycin C repair exonuclease MrfB.

Author

Manthei KA, Munson LM, Nandakumar J, and Simmons LA

Abstract

Mitomycin C (MMC) repair factor A ( mrfA ) and factor B ( mrfB ), encode a conserved helicase and exonuclease that repair DNA damage in the soil-dwelling bacterium Bacillus subtilis . Here we have focused on the characterization of MrfB, a DEDDh exonuclease in the DnaQ superfamily. We solved the structure of the exonuclease core of MrfB to a resolution of 2.1 Å, in what appears to be an inactive state. In this conformation, a predicted α-helix containing the catalytic DEDDh residue Asp172 adopts a random coil, which moves Asp172 away from the active site and results in the occupancy of only one of the two catalytic Mg 2+ ions. We propose that MrfB resides in this inactive state until it interacts with DNA to become activated. By comparing our structure to an AlphaFold prediction as well as other DnaQ-family structures, we located residues hypothesized to be important for exonuclease function. Using exonuclease assays we show that MrfB is a Mg 2+ -dependent 3'-5' DNA exonuclease. We show that Leu113 aids in coordinating the 3' end of the DNA substrate, and that a basic loop is important for substrate binding. This work provides insight into the function of a recently discovered bacterial exonuclease important for the repair of MMC-induced DNA adducts.

Published
2024
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23. Determinants of pH profile and acyl chain selectivity in lysosomal phospholipase A 2 .

Author

Hinkovska-Galcheva V, Kelly R, Manthei KA, Bouley R, Yuan W, Schwendeman A, Tesmer JJG, and Shayman JA

Subjects
Acylation, Humans, Hydrogen-Ion Concentration, Hydrolysis, Models, Molecular, Mutation, Phospholipases A2 chemistry, Phospholipases A2 genetics, Protein Structure, Tertiary, Substrate Specificity, Lysosomes enzymology, Phospholipases A2 metabolism
Abstract

Lysosomal phospholipase A2 (LPLA 2 ) is characterized by broad substrate recognition, peak activity at acidic pH, and the transacylation of lipophilic alcohols, especially N -acetyl-sphingosine. Prior structural analysis of LPLA 2 revealed the presence of an atypical acidic residue, Asp13, in the otherwise hydrophobic active site cleft. We hypothesized that Asp13 contributed to the pH profile and/or substrate preference of LPLA 2 for unsaturated acyl chains. To test this hypothesis, we substituted Asp13 for alanine, cysteine, or phenylalanine; then, we monitored the formation of 1- O -acyl- N -acetylsphingosine to measure the hydrolysis of sn -1 versus sn -2 acyl groups on a variety of glycerophospholipids. Substitutions with Asp13 yielded significant enzyme activity at neutral pH (7.4) and perturbed the selectivity for mono- and double-unsaturated acyl chains. However, this position played no apparent role in selecting for either the acyl acceptor or the head group of the glycerophospholipid. Our modeling indicates that Asp13 and its substitutions contribute to the pH activity profile of LPLA 2 and to acyl chain selectivity by forming part of a hydrophobic track occupied by the scissile acyl chain., (Copyright © 2018 Hinkovska-Galcheva et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.)

Published
2018
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