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2. Deciphering pathophysiological mechanisms underlying cystathionine beta-synthase-deficient homocystinuria using targeted metabolomics, liver proteomics, sphingolipidomics and analysis of mitochondrial function

Author

Majtan, Tomas, Olsen, Thomas, Sokolova, Jitka, Krijt, Jakub, Křížková, Michaela, Ida, Tomoaki, Ditrói, Tamás, Hansikova, Hana, Vit, Ondrej, Petrak, Jiri, Kuchař, Ladislav, Kruger, Warren D., Nagy, Péter, Akaike, Takaaki, and Kožich, Viktor

Published
2024
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3. CRY1‐CBS binding regulates circadian clock function and metabolism

Author

Cal‐Kayitmazbatir, Sibel, Kulkoyluoglu‐Cotul, Eylem, Growe, Jacqueline, Selby, Christopher P, Rhoades, Seth D, Malik, Dania, Oner, Hasimcan, Asimgil, Hande, Francey, Lauren J, Sancar, Aziz, Kruger, Warren D, Hogenesch, John B, Weljie, Aalim, Anafi, Ron C, and Kavakli, Ibrahim Halil

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Nutrition, Sleep Research, 1.1 Normal biological development and functioning, Underpinning research, Metabolic and endocrine, ARNTL Transcription Factors, Amino Acid Sequence, Animals, CLOCK Proteins, Circadian Clocks, Circadian Rhythm, Cryptochromes, Cystathionine beta-Synthase, E-Box Elements, Female, HEK293 Cells, Humans, Male, Metabolic Networks and Pathways, Metabolome, Mice, Mice, Knockout, Mutation, Period Circadian Proteins, Protein Binding, Protein Processing, Post-Translational, Sequence Alignment, Sequence Homology, Amino Acid, Signal Transduction, circadian rhythms, cryptochrome, intrinsically disordered protein, CON NMR, delayed sleep phase disorder, Transcription, Genetic, Protein Domains
Abstract

Circadian rhythms are generated by interlocked transcription-translation feedback loops that establish cell-autonomous biological timing of ∼24 h. Mutations in core clock genes that alter their stability or affinity for one another lead to changes in circadian period. The human CRY1Δ11 mutant lengthens circadian period to cause delayed sleep phase disorder (DSPD), characterized by a very late onset of sleep. CRY1 is a repressor that binds to the transcription factor CLOCK:BMAL1 to inhibit its activity and close the core feedback loop. We previously showed how the PHR (photolyase homology region) domain of CRY1 interacts with distinct sites on CLOCK and BMAL1 to sequester the transactivation domain from coactivators. However, the Δ11 variant alters an intrinsically disordered tail in CRY1 downstream of the PHR. We show here that the CRY1 tail, and in particular the region encoded by exon 11, modulates the affinity of the PHR domain for CLOCK:BMAL1. The PHR-binding epitope in exon 11 is necessary and sufficient to disrupt the interaction between CRY1 and the subunit CLOCK. Moreover, PHR-tail interactions are conserved in the paralog CRY2 and reduced when either CRY is bound to the circadian corepressor PERIOD2. Discovery of this autoregulatory role for the mammalian CRY1 tail and conservation of PHR-tail interactions in both mammalian cryptochromes highlights functional conservation with plant and insect cryptochromes, which also utilize PHR-tail interactions to reversibly control their activity.

Published
2021

4. An orally administered enzyme therapeutic for homocystinuria that suppresses homocysteine by metabolizing methionine in the gastrointestinal tract

Author

Skvorak, Kristen, Mitchell, Vesna, Teadt, Leann, Franklin, Kierra A., Lee, Hyung-Ok, Kruse, Nikki, Huitt-Roehl, Callie, Hang, Julie, Du, Faye, Galanie, Stephanie, Guan, Steven, Aijaz, Hera, Zhang, Nianliu, Rajkovic, Gabriel, Kruger, Warren D., Ismaili, Moulay Hicham Alaoui, Huisman, Gjalt, McCluskie, Kerryn, and Silverman, Adam P.

Published
2023
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7. Impact of primary sequence changes on the self‐association properties of mammalian cystathionine beta‐synthase enzymes.

Author

Lee, Hyung‐Ok, Gupta, Kushol, Wang, Liqun, Dunbrack, Roland L., Majtan, Tomas, and Kruger, Warren D.

Abstract

Cystathionine beta‐synthase (CBS) is an evolutionarily conserved enzyme that plays a key role in mammalian sulfur amino acid biochemistry, mutations in which are the cause of classical homocystinuria (HCU), an inborn error of metabolism. Although there is agreement in the literature that CBS is a homomultimer, its precise structure is a source of confusion. Here, we performed a series of experiments examining the quaternary structure of various wild‐type and mutant CBS enzymes using a combination of native gel electrophoresis, in situ activity assays, analytical ultracentrifugation, and gel filtration. Our data show that recombinantly expressed and purified full‐length wild‐type human CBS enzyme (hCBS) and HCU‐causing variants (p.P422L, p.I435T, and p.R125Q CBS) form high molecular weight assemblies that are consistent with the properties expected of a filament. The filament is enzymatically active, and its size is sensitive to protein concentration. This behavior contrasts sharply with hCBS enzymes containing small deletions within the Bateman domain, which form stable tetramers and octamers regardless of concentration. Examination of liver lysates from humans and mice confirms the existence of enzymatically active high molecular weight aggregates in vivo, but also shows that these aggregates are specific to human CBS and do not occur in mice. Molecular modeling using AlphaFold2 suggests that these experimentally observed differences may be explained by subtle differences in the interaction mediated by the Bateman domains. Our results show that small differences in amino acid sequence can cause large differences in the size and shape of CBS multimers. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Author Correction: Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation

Author

Padmanabhan, Nisha, Kyon, Huang Kie, Boot, Arnoud, Lim, Kevin, Srivastava, Supriya, Chen, Shuwen, Wu, Zhiyuan, Lee, Hyung-Ok, Mukundan, Vineeth T., Chan, Charlene, Chan, Yarn Kit, Xuewen, Ong, Pitt, Jason J., Isa, Zul Fazreen Adam, Xing, Manjie, Lee, Ming Hui, Tan, Angie Lay Keng, Ting, Shamaine Ho Wei, Luftig, Micah A., Kappei, Dennis, Kruger, Warren D., Bian, Jinsong, Ho, Ying Swan, Teh, Ming, Rozen, Steve George, and Tan, Patrick

Published
2021
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11. Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation

Author

Padmanabhan, Nisha, Kyon, Huang Kie, Boot, Arnoud, Lim, Kevin, Srivastava, Supriya, Chen, Shuwen, Wu, Zhiyuan, Lee, Hyung-Ok, Mukundan, Vineeth T., Chan, Charlene, Chan, Yarn Kit, Xuewen, Ong, Pitt, Jason J., Isa, Zul Fazreen Adam, Xing, Manjie, Lee, Ming Hui, Tan, Angie Lay Keng, Ting, Shamaine Ho Wei, Luftig, Micah A., Kappei, Dennis, Kruger, Warren D., Bian, Jinsong, Ho, Ying Swan, Teh, Ming, Rozen, Steve George, and Tan, Patrick

Published
2021
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16. Supplemental Table 4 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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17. Supplemental Table 3 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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18. Supplemental Tables 5-7 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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19. Supplemental Table 1 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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20. Data from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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21. Supplementary Figures from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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22. Key Resources Table from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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23. Supplemental Table 8 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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24. Supplemental Table 2 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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30. Supplementary Figures 1-3, Table 1 from Mice Heterozygous for Germ-line Mutations in Methylthioadenosine Phosphorylase (MTAP) Die Prematurely of T-Cell Lymphoma

Author

Kadariya, Yuwaraj, primary, Yin, Bu, primary, Tang, Baiqing, primary, Shinton, Susan A., primary, Quinlivan, Eoin P., primary, Hua, Xiang, primary, Klein-Szanto, Andres, primary, Al-Saleem, Tahseen I., primary, Bassing, Craig H., primary, Hardy, Richard R., primary, and Kruger, Warren D., primary

Published
2023
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31. Supplementary Figure Legends 1-3 from Mice Heterozygous for Germ-line Mutations in Methylthioadenosine Phosphorylase (MTAP) Die Prematurely of T-Cell Lymphoma

Author

Kadariya, Yuwaraj, primary, Yin, Bu, primary, Tang, Baiqing, primary, Shinton, Susan A., primary, Quinlivan, Eoin P., primary, Hua, Xiang, primary, Klein-Szanto, Andres, primary, Al-Saleem, Tahseen I., primary, Bassing, Craig H., primary, Hardy, Richard R., primary, and Kruger, Warren D., primary

Published
2023
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37. Examination of two different proteasome inhibitors in reactivating mutant human cystathionine β-synthase in mice.

Author

Gupta, Sapna, Lee, Hyung-Ok, Wang, Liqun, and Kruger, Warren D.

Subjects
PROTEASOME inhibitors, HEAT shock proteins, CYSTATHIONINE, LIVER proteins, MOLECULAR chaperones, INBORN errors of metabolism, PROTEASE inhibitors
Abstract

Classic homocystinuria is an inborn error of metabolism caused mainly by missense mutations leading to misfolded and/or unstable human cystathionine β-synthase (CBS) protein, causing the accumulation of excess total homocysteine (tHcy) in tissues. Previously, it has been shown that certain missense containing human CBS proteins can be functionally rescued in mouse models of CBS deficiency by treatment with proteasome inhibitors. The rescue by proteasome inhibitors is thought to work both by inhibiting the degradation of misfolded CBS protein and by inducing the levels of heat-shock chaperone proteins in the liver. Here we examine the effectiveness of two FDA approved protease inhibitors, carfilzomib and bortezomib, on various transgenic mouse models of human CBS deficiency. Our results show that although both drugs are effective in inducing the liver chaperone proteins Hsp70 and Hsp27, and are effective in inhibiting proteasome function, bortezomib was somewhat more robust in restoring the mutant CBS function. Moreover, there was no significant correlation between proteasome inhibition and CBS activity, suggesting that some of bortezomib's effects are via other mechanisms. We also test the use of low-doses of bortezomib and carfilzomib on various mouse models for extended periods of time and find that while low-doses are less toxic, they are also less effective at restoring CBS function. Overall, these results show that while restoration of mutant CBS function is possible with proteasome inhibitors, the exact mechanism is complicated and it will likely be too toxic for long-term patient treatment. [ABSTRACT FROM AUTHOR]

Published
2023
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39. Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Department of Biology, Francescone, Ralph, Barbosa Vendramini-Costa, Débora, Franco-Barraza, Janusz, Wagner, Jessica, Muir, Alexander, Lau, Allison N., Gabitova, Linara, Pazina, Tatiana, Gupta, Sapna, Luong, Tiffany, Rollins, Dustin, Malik, Ruchi, Thapa, Roshan J., Restifo, Diana, Zhou, Yan, Cai, Kathy Q., Hensley, Harvey H., Tan, Yinfei, Kruger, Warren D., Devarajan, Karthik, Balachandran, Siddharth, Klein-Szanto, Andres J., Wang, Huamin, El-Deiry, Wafik S., Vander Heiden, Matthew G., Peri, Suraj, Campbell, Kerry S., Astsaturov, Igor, Cukierman, Edna, Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Department of Biology, Francescone, Ralph, Barbosa Vendramini-Costa, Débora, Franco-Barraza, Janusz, Wagner, Jessica, Muir, Alexander, Lau, Allison N., Gabitova, Linara, Pazina, Tatiana, Gupta, Sapna, Luong, Tiffany, Rollins, Dustin, Malik, Ruchi, Thapa, Roshan J., Restifo, Diana, Zhou, Yan, Cai, Kathy Q., Hensley, Harvey H., Tan, Yinfei, Kruger, Warren D., Devarajan, Karthik, Balachandran, Siddharth, Klein-Szanto, Andres J., Wang, Huamin, El-Deiry, Wafik S., Vander Heiden, Matthew G., Peri, Suraj, Campbell, Kerry S., Astsaturov, Igor, and Cukierman, Edna

Abstract

© 2020 American Association for Cancer Research. Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multiplex data from patient tissue, three-dimensional coculturing in vitro assays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. We found that NetG1+ cancer-associated fibroblasts (CAF) support PDAC survival, through a NetG1-mediated effect on glutamate/glutamine metabolism. Also, NetG1+ CAFs are intrinsically immunosup-pressive and inhibit natural killer cell–mediated killing of tumor cells. These protumor functions are controlled by a signaling circuit downstream of NetG1, which is comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally, blocking NetG1 with a neutral-izing antibody stunts in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC. SIGNIFICANCE: This study demonstrates the feasibility of targeting a fibroblastic protein, NetG1, which can limit PDAC tumorigenesis in vivo by reverting the protumorigenic properties of CAFs. Moreover, inhibition of metabolic proteins in CAFs altered their immunosuppressive capacity, linking metabolism with immunomodulatory function.

Published
2022

40. Aberrant cyclin C nuclear release induces mitochondrial fragmentation and dysfunction in MED13L syndrome fibroblasts

Author

Metabole ziekten patientenzorg, Child Health, Infection & Immunity, Chang, Kai Ti, Jezek, Jan, Campbell, Alicia N., Stieg, David C., Kiss, Zachary A., Kemper, Kevin, Jiang, Ping, Lee, Hyung Ok, Kruger, Warren D., van Hasselt, Peter M., Strich, Randy, Metabole ziekten patientenzorg, Child Health, Infection & Immunity, Chang, Kai Ti, Jezek, Jan, Campbell, Alicia N., Stieg, David C., Kiss, Zachary A., Kemper, Kevin, Jiang, Ping, Lee, Hyung Ok, Kruger, Warren D., van Hasselt, Peter M., and Strich, Randy

Published
2022

49. Recent therapeutic approaches to cystathionine beta‐synthase‐deficient homocystinuria.

Author

Majtan, Tomas, Kožich, Viktor, and Kruger, Warren D.

Subjects
AMINO acid metabolism disorders, CYSTATHIONINE, THERAPEUTICS, METHIONINE metabolism
Abstract

Cystathionine beta‐synthase (CBS)‐deficient homocystinuria (HCU) is the most common inborn error of sulfur amino acid metabolism. The pyridoxine non‐responsive form of the disease manifests itself by massively increasing plasma and tissue concentrations of homocysteine, a toxic intermediate of methionine metabolism that is thought to be the major cause of clinical complications including skeletal deformities, connective tissue defects, thromboembolism and cognitive impairment. The current standard of care involves significant dietary interventions that, despite being effective, often adversely affect quality of life of HCU patients, leading to poor adherence to therapy and inadequate biochemical control with clinical complications. In recent years, the unmet need for better therapeutic options has resulted in development of novel enzyme and gene therapies and exploration of pharmacological approaches to rescue CBS folding defects caused by missense pathogenic mutations. Here, we review scientific evidence and current state of affairs in development of recent approaches to treat HCU. [ABSTRACT FROM AUTHOR]

Published
2023
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