Targeting Epigenetic Changes Mediated by Members of the SMYD Family of Lysine Methyltransferases
Abstract
:1. Introduction
2. Approaches to the Development of Pharmacologic Agents Modulating SMYD Function
2.1. Inhibitor Development Based on Structure–Activity Relationships (SAR)
2.2. In Silico Methods for Inhibitor Identification to Structurally Known Proteins
3. SMYD-Proteins, Structure, Function, and Medicinal Potential
3.1. SMYD1
3.1.1. Structure and Function of SMYD1
3.1.2. Therapeutic Applications, Potential Drug Targeting, and the Use of SMYD1 as a Prognostic Indicator
3.2. SMYD2
3.2.1. Structure and Function of SMYD2
3.2.2. Therapeutic Applications, Potential Drug Targeting, and Prognostics SMYD2
3.3. SMYD3
3.3.1. Structure and Function of SMYD3
3.3.2. Therapeutic Applications, Potential Drug Targeting of SMYD3 and the Prognostic Value of SMYD3
3.4. SMYD4
3.4.1. Structure and Function of SMYD4
3.4.2. Therapeutic Applications, Potential Drug Targeting and Prognostics of SMYD4
3.5. SMYD5
Structure and Function of SMYD5
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Enzyme and Date of Discovery | AA Length | X-ray Structure Solved | Regulating Cellular Pathways | Histone Substrate | Inhibitors | Linked to Diseases | Special Features |
---|---|---|---|---|---|---|---|
SMYD1 1995 | 472 [2,6] | Yes SET divided by MYND [29,45,64,65,66,67] | Reduced methylation of cardio endoplasmic reticulum stress metabolic sensor, TRB3, [16,17,18] cardiomyocyte differentiation. Muscle-specific for cardiac function. | H3k4, H3K9, H3K27, and H4K20 [1,26] H9c2 rat myoblasts [71] | Breast cancer [72] Cardiac diseases [17] | Multiple isoforms in cardiac and skeletal muscle tissue [16,18] Early heart development [17] Prostate cancer [19] | |
SMYD2 | 433 [6] | Yes SET divided by MYND [29,45,64,65,66,67] | Negative regulator of macrophage activation, MI polarization. Lowered inerleukin-6 (IL-6), tumor necrosis factor alpha (TNFα) and other proinflammatory cytokine differentiation of the mesendoderm [73,74]. SMYD2 as an oncogene [75]. | H3K4 methyltransferase related to H3K4me2,3 H3K36 [76,77]. | AZ50552 [45] A-89361 [54] LLY-50762 [55] | Liver, kidneys, thymus, hypothalamus, vomeronasal organ (VNO), and ovaries [78] Liver hematomas Leukemias such as CML, ALL, B-ALL, MLLr-B-ALL, AML, and T-ALL [75] gastric cancers [79] | Selective for lysine methylation on histone and non-histone proteins such as retinoblastoma protein (RB) and tumor suppressors (p53) [73,74] |
SMYD3 | SMYD3 | Yes [29,31,68,69] | Heart and skeletal development, as well as multiple dysfunctional health pathways. [68] | H3K4 Hepatocellular, colon, and breast carcinoma regulator [31] | BCI-121, EPZ031686, EPZ030456, EPZ028862, GSK-49, BAY-6035. EP2031686 [31] | Hepatocellular malignancies [31] | Establish a method for trimethylation of genetic sequences [43] |
SMYD4 | 854 [6] | No [29]. | Tumor suppression [6,61,80] | Unknown [6] | Unknown [6] | Zebrafish [81,82] using Drosophila SMYD4 (dSMYD4) [77,81] | Congenital heart defects, [81] rheumatoid arthritis [3] autoimmune disease [83] |
SMYD5 | 4 [6] | No [70,84] | Repression of cytokine transcription of genes [3,4,85]. Self-renewal of embryonic stem cells (ESC) [86]. | H4K20me3 [86] H3K36 and H3K37 [4] H3L36me3 [5] H3K9 [87] | Zebrafish model [88] | Hepatocellular carcinomas [84] |
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Padilla, A.; Manganaro, J.F.; Huesgen, L.; Roess, D.A.; Brown, M.A.; Crans, D.C. Targeting Epigenetic Changes Mediated by Members of the SMYD Family of Lysine Methyltransferases. Molecules 2023, 28, 2000. https://doi.org/10.3390/molecules28042000
Padilla A, Manganaro JF, Huesgen L, Roess DA, Brown MA, Crans DC. Targeting Epigenetic Changes Mediated by Members of the SMYD Family of Lysine Methyltransferases. Molecules. 2023; 28(4):2000. https://doi.org/10.3390/molecules28042000
Chicago/Turabian StylePadilla, Alyssa, John F. Manganaro, Lydia Huesgen, Deborah A. Roess, Mark A. Brown, and Debbie C. Crans. 2023. "Targeting Epigenetic Changes Mediated by Members of the SMYD Family of Lysine Methyltransferases" Molecules 28, no. 4: 2000. https://doi.org/10.3390/molecules28042000