Abstract
Experimental studies have shown that many glycolytic enzymes bind cytoskeletal proteins reversibly including lactate dehydrogenase (LDH) and that the interaction may be electrostatic in nature. LDH is particularly interesting because different isoforms have different binding affinities. Herein, Brownian dynamics simulations examine the interactions of mixed LDH isoforms with F-actin based on models of human muscle (M) and heart (H) isoforms and rabbit muscle (M) and heart (H) isoforms built via homology modeling from a variety of mammalian forms of the enzyme. The LDH-mixed tetrameric isoforms, LDH-M3H, LDH-M2H2, LDH-MH3, give distinctive electrostatic potentials and charges; + 6.9 e for human LDH-M3H, −9.4 e for human LDH-MH3, the LDH-M2H2 gives three distinctively different pictures of the electrostatic potential and show different binding affinity depending on the nature of the quaternary structure of the tetramer. If the positive charge patch of LDH-M4 between subunits A/D and subunits B/C, which was identified as the binding site of LDH to F-actin for the muscle isoform (Part I of the companion paper), remains intact on one side of LDH-M2H2, the mixed isoform can still bind F-actin. If, however, the LDH-M2H2 isoform does not maintain this positively charged patch, the mixed isoform does not bind as strongly.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alekseeva AE, Potapkina TA, Prozorovskii VN (1990) Antipeptide antibodies, specific to N-terminal site of lactate dehydrogenase from pig muscle tissue. Vopr Med Khim 36:45–47
Boeckmann B, Bairoch A, Apweiler R, Blatter M-C, Estreicher A, Gasteiger E, Martin MJ, Michoud K, O’Donovan C, Phan I, Pilbout S, Schneider M (2003) The SWISS-PROT protein knowledgebase and its supplement TrEMBL in 2003. Nucleic Acids Res 31(1):365–370. https://doi.org/10.1093/nar/gkg095
Bronstein WW, Knull HR (1981) Interaction of muscle glycolytic enzymes with thin filament proteins. Can J Biochem 59(7):494–499. https://doi.org/10.1139/o81-069
Dunn CR, Wilks HM, Halsall DJ, Atkinson T, Clarke AR, Muirhead H, Holbrook JJ (1991) Design and synthesis of new enzymes based on the lactate dehydrogenase framework. Philos Trans R Soc B 332(1263):177–184. https://doi.org/10.1098/rstb.1991.0047
Favero TG, Stavrianea SS, Klug AGA (1999) Training-induced alterations in lactate dehydrogenase reaction kinetics in rats: a re-examination. Exp Physiol 84(5):989–998. https://doi.org/10.1111/j.1469-445X.1999.01886.x
Forlemu NY, Waingeh VF, Ouporov IV, Lowe SL, Thomasson KA (2007) Theoretical study of interactions between muscle aldolase and F-actin: Insight into different species. Biopolymers 85(1):60–71. https://doi.org/10.1002/bip.20611
Gilmour M, Flint HJ, Mitchell WJ (1994) Multiple lactate dehydrogenase activities of the rumen bacterium Selenomonas ruminantium. Microbiology (Reading, England) 140(Pt 8):2077–2084
Goto T, Sugawara K, Nakamura S, Kidokoro S-I, Wakui H, Nunomura W (2016) Enzymatic and thermodynamic profiles of a heterotetramer lactate dehydrogenase isozyme in swine. Biochem Biophys Res Commun 479(4):860–867. https://doi.org/10.1016/j.bbrc.2016.09.118
Haschke RH, Heilmeyer J, Meyer F, Fischer EH (1970) Control of phosphorylase activity in a muscle glycogen particle. 3. Regulation of phosphorylase phosphatase. J Bio Chem 245(24):6657–6663
Kiltz HH, Keil W, Griesbach M, Petry K, Meyer H (1977) The primary structure of porcine lactate dehydrogenase: isoenzymes M4 and H4. Hoppe-Seyler’s Zeitschrift Fuer Physiologische Chemie 358:123–127
Liu J, Chen G, Liu Z, Liu S, Cai Z, You P, Ke Y, Lai L, Huang Y, Gao H, Zhao L, Pelicano H, Huang P, McKeehan WL, Wu C-L, Wang C, Zhong W, Wang F (2018) Aberrant FGFR tyrosine kinase signaling enhances the Warburg Effect by reprogramming LDH isoform expression and activity in prostate cancer. Cancer Res 78(16):4459–4470. https://doi.org/10.1158/0008-5472.can-17-3226
Lluis C (1985) Lactate dehydrogenase binding to the mitochondrial fraction and to a mitochondrial inhibitor as a function of the isoenzymatic composition. Int J Biochem 17:1219–1226
Lowe SL, Atkinson DM, Waingeh VF, Thomasson KA (2002) Brownian dynamics of interactions between aldolase mutants and F-actin. J Mol Recognit 15(6):423–431. https://doi.org/10.1002/jmr.599
Millan JL, Driscoll CE, Levan KM, Goldberg E (1987) Epitopes of human testis-specific lactate dehydrogenase deduced from a cDNA sequence. Proc Natl Acad Sci USA 84(15):5311–5315. https://doi.org/10.1073/pnas.84.15.5311
Njabon EN, Patouossa I, Carlson KL, Lowe SL, Forlemu NY, Thomasson KA (2020) Brownian Dynamics simulations of the interactions between lactate dehydrogenase (LDH) and G- or F-Actin. Part I: muscle and heart homo-isoforms. Scientific African 9:e00510. https://doi.org/10.1016/j.sciaf.2020.e00510
Northrup SH, Laugher T, Stevenson G (1997) MacroDox macromolecular simulation program
Ouporov IV, Knull HR, Thomasson KA (1999) Brownian dynamics simulations of interactions between aldolase and G- or F-Actin. Biophys J 76(1):17–27. https://doi.org/10.1016/S0006-3495(99)77174-2
Ouporov IV, Knull HR, Lowe SL, Thomasson KA (2001) Interactions of glyceraldehyde-3-phosphate dehydrogenase with G- and F-actin predicted by Brownian dynamics. J Mol Recognit 14(1):29–41. https://doi.org/10.1002/1099-1352(200101/02)14:1%3c29::AID-JMR517%3e3.0.CO;2-T
Pettersson H, Pettersson G (1999) Mechanism of metabolite transfer in coupled two-enzyme reactions involving aldolase. Eur J Biochem 262(2):371–376. https://doi.org/10.1046/j.1432-1327.1999.00386.x
Read JA, Winter VJ, Eszes CM, Sessions RB, Brady RL (2001) Structural basis for altered activity of M- and H-isozyme forms of human lactate dehydrogenase. Proteins 43(2):175–185. https://doi.org/10.1002/1097-0134(20010501)43:2%3c175::AID-PROT1029%3e3.0.CO;2-#
Srere PA, Mosbach K (1974) Metabolic compartmentation: Symbiotic, organellar, multienzymic, and microenvironmental. Annu Rev Microbiol 28(1):61–84. https://doi.org/10.1146/annurev.mi.28.100174.000425
Stephan P, Clarke F, Morton D (1986) The indirect binding of triose-phosphate isomerase to myofibrils to form a glycolytic enzyme mini-complex. Biochem Biophys Acta 873:127–135
Takeno T, Li SS (1989) Structure of the human lactate dehydrogenase B gene. Biochem J 257(3):921–924. https://doi.org/10.1042/bj2570921
Tanford C, Kirkwood JG (1957) Theory of Protein titration curves. I. General equations for impenetrable spheres. J Am Chem Soc 79(20):5333–5339. https://doi.org/10.1021/ja01577a001
Tsoi SC-M, Li JY, Mannen H, Li SS-L (1998) Molecular evolution of vertebrate lactate dehydrogenase isozymes by gene duplication. EMBL/GenBank/DDBJ Databases
Tsuji S, Qureshi MA, Hou EW, Fitch WM, Li SS (1994) Evolutionary relationships of lactate dehydrogenases (LDHs) from mammals, birds, an amphibian, fish, barley, and bacteria: LDH cDNA sequences from Xenopus, pig, and rat. Proc Natl Acad Sci USA 91(20):9392–9396. https://doi.org/10.1073/pnas.91.20.9392
Volker KW, Knull HR (1997) A glycolytic enzyme binding domain on tubulin. Arch Biochem Biophys 338(2):237–243. https://doi.org/10.1006/abbi.1996.9819
Waingeh VF, Lowe SL, Thomasson KA (2004) Brownian dynamics of interactions between glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mutants and F-actin. Biopolymers 73(5):533–541. https://doi.org/10.1002/bip.10560
Wang J, Tolan DR, Pagliaro L (1997) Metabolic compartmentation in living cells: structural association of aldolase. Exp Cell Res 237(2):445–451. https://doi.org/10.1006/excr.1997.3811
Westbrook J, Feng Z, Jain S, Bhat TN, Thanki N, Ravichandran V, Gilliland GL, Bluhm W, Weissig H, Greer DS, Bourne PE, Berman HM (2002) The protein data bank: unifying the archive. Nucleic Acids Res 30(1):245–248. https://doi.org/10.1093/nar/30.1.245
Funding
This research was funded by NIH/INBRE and the North Dakota Computational Chemistry and Biology Network for computational resources and NIH/NIGMS Grant No. 2 R15 GM055929‐03 and ND EPSCoR.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Njabon, E.N., Forlemu, N.Y., Emadak, A. et al. Brownian dynamics simulations of the interactions between lactate dehydrogenase (LDH) and G- or F-actin. Part II: mixed isoforms. Chem. Pap. 75, 1937–1948 (2021). https://doi.org/10.1007/s11696-020-01463-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11696-020-01463-0