About

Sergey A. Krupenko, PhD, is a Professor of Nutrition at the UNC Gillings School of Global Public Health. His research focuses on enzymes regulating folate metabolism, which are crucial for understanding cellular processes related to disease treatment and prevention. Dr. Krupenko studies the biochemical mechanisms underlying folate metabolism and its implications for cancer and other health conditions. He holds a B.S. in Biochemistry from Byelorussian State University and a Degree of Candidate of Science in Biochemistry from the Institute of Bioorganic Chemistry, Byelorussian Academy of Science. His academic and research career has contributed to uncovering the structure and function of enzymes involved in cellular proliferation and cancer, with notable work on the regulation of tumor-suppressor proteins and cellular motility. Dr. Krupenko's expertise and research have advanced understanding in the field of nutritional biochemistry and its role in disease processes.

Research topics

• Biology
• Biochemistry
• Endocrinology
• Genetics
• Chemistry
• Internal medicine
• Cell biology
• Cancer research
• Medicine
• Bioinformatics

Selected publications

• Dietary folate supplementation modifies effects of arsenic exposure on DNA methylation profiles in sperm of mice expressing the human AS3MT

  Archives of Toxicology · 2026-03-10

  article
  PublisherDOI

• Clinical Implications of 10-Formyltetrahydrofolate Dehydrogenase Expression in Hormone Receptor-Positive Breast Cancer

  SSRN Electronic Journal · 2025-01-01

  preprintOpen accessSenior author
  PublisherDOI

• Differential Expression of One‐Carbon Pathway Enzyme <scp>ALDH1L1</scp> Is Linked to Tumorigenicity of Low‐Grade Bladder Cancer Cells Through Metabolic Reprogramming

  Cancer Medicine · 2025-10-01

  articleOpen accessSenior authorCorresponding

  BACKGROUND: RT4 bladder cancer cell line, derived from a nonmuscle-invasive low-grade subtype, is one of the few neoplastic cell lineages that maintain high expression of the candidate tumor suppressor ALDH1L1. Here, we investigated how differential ALDH1L1 expression affects cellular characteristics and tumorigenicity of RT4 cells as well as tumor metabotypes. METHODS: We characterized RT4 cells and two shRNA clones (sh506/low ALDH1L1 expression; sh572/ALDH1L1 is lost) for proliferation, migration, clonogenic capacity, and mitochondrial respiration. We have further evaluated the tumorigenic potential of RT4 cells and the two clones in nude mice and compared metabotypes of derived tumors using untargeted metabolomics. RESULTS: Both clones with diminished ALDH1L1 expression exhibited increased proliferation rates with doubling times of 19.4 h (sh506) and 23.2 h (sh572) versus 36.3 h for RT4 cells. Downregulation of ALDH1L1 expression also enhanced motility and clonogenic capacity. Proliferation and clonogenic capacity were highest for the sh506 clone (low ALDH1L1 expression), while motility was strongest for the sh572 clone (complete ALDH1L1 loss). Both clones showed altered energy metabolism, as indicated by a reduced basal oxygen consumption rate and enhanced maximal respiration rate following oligomycin treatment. Mouse xenograft tumors derived from ALDH1L1-deficient RT4 clones were significantly larger than RT4 cell-derived tumors. Of note, complete ALDH1L1 loss (sh572 clone) was less advantageous for tumor growth than the partial loss of the protein (sh506 clone). Untargeted metabolomics has shown that tumors with downregulated ALDH1L1 have altered the metabolism of fatty acids, amino acids, CoA, and acylcarnitines. Alterations in several key pathways, including glutathione metabolism (sh506), and TCA cycle (sh572), depend on the extent of ALDH1L1 downregulation. CONCLUSIONS: Our study underscores ALDH1L1 as a key metabolic regulator of proliferation, migration, and tumorigenicity in RT4 bladder cancer cells, suggesting that retaining low ALDH1L1 expression can provide a metabolic advantage for growth of aggressive tumors.

  PublisherOA PDFDOI

• 799 Dissecting the role of folate receptor beta-mediated one-carbon metabolism in tumor-associated macrophages

  Regular and Young Investigator Award Abstracts · 2025-11-01

  articleOpen access
  PublisherOA PDFDOI

• Differential Expression of One‐Carbon Pathway Enzyme ALDH1L1 Is Linked to Tumorigenicity of Low‐Grade Bladder Cancer Cells Through Metabolic Reprogramming

  UNC Libraries · 2025-12-17

  articleOpen access

  RT4 bladder cancer cell line, derived from a nonmuscle‐invasive low‐grade subtype, is one of the few neoplastic cell lineages that maintain high expression of the candidate tumor suppressor ALDH1L1. Here, we investigated how differential ALDH1L1 expression affects cellular characteristics and tumorigenicity of RT4 cells as well as tumor metabotypes. We characterized RT4 cells and two shRNA clones (sh506/low ALDH1L1 expression; sh572/ALDH1L1 is lost) for proliferation, migration, clonogenic capacity, and mitochondrial respiration. We have further evaluated the tumorigenic potential of RT4 cells and the two clones in nude mice and compared metabotypes of derived tumors using untargeted metabolomics. Both clones with diminished ALDH1L1 expression exhibited increased proliferation rates with doubling times of 19.4 h (sh506) and 23.2 h (sh572) versus 36.3 h for RT4 cells. Downregulation of ALDH1L1 expression also enhanced motility and clonogenic capacity. Proliferation and clonogenic capacity were highest for the sh506 clone (low ALDH1L1 expression), while motility was strongest for the sh572 clone (complete ALDH1L1 loss). Both clones showed altered energy metabolism, as indicated by a reduced basal oxygen consumption rate and enhanced maximal respiration rate following oligomycin treatment. Mouse xenograft tumors derived from ALDH1L1‐deficient RT4 clones were significantly larger than RT4 cell‐derived tumors. Of note, complete ALDH1L1 loss (sh572 clone) was less advantageous for tumor growth than the partial loss of the protein (sh506 clone). Untargeted metabolomics has shown that tumors with downregulated ALDH1L1 have altered the metabolism of fatty acids, amino acids, CoA, and acylcarnitines. Alterations in several key pathways, including glutathione metabolism (sh506), and TCA cycle (sh572), depend on the extent of ALDH1L1 downregulation. Our study underscores ALDH1L1 as a key metabolic regulator of proliferation, migration, and tumorigenicity in RT4 bladder cancer cells, suggesting that retaining low ALDH1L1 expression can provide a metabolic advantage for growth of aggressive tumors.

  PublisherDOI

• Exploratory Metabolomics Underscores the Folate Enzyme ALDH1L1 as a Regulator of Glycine and Methylation Reactions

  UNC Libraries · 2025-07-26

  articleOpen access

  Folate (vitamin B9) is involved in one-carbon transfer reactions and plays a significant role in nucleic acid synthesis and control of cellular proliferation, among other key cellular processes. It is now recognized that the role of folates in different stages of carcinogenesis is complex, and more research is needed to understand how folate reactions become dysregulated in cancers and the metabolic consequences that occur as a result. ALDH1L1 (cytosolic 10-formyltetrahydrofolate dehydrogenase), an enzyme of folate metabolism expressed in many tissues, is ubiquitously downregulated in cancers and is not expressed in cancer cell lines. The RT4 cell line (derived from papillary bladder cancer) which expresses high levels of ALDH1L1 represents an exception, providing an opportunity to explore the metabolic consequences of the loss of this enzyme. We have downregulated this protein in RT4 cells (shRNA driven knockdown or CRISPR driven knockout) and compared metabolomes of ALDH1L1-expressing and -deficient cells to determine if metabolic changes linked to the loss of this enzyme might provide proliferative and/or survival advantages for cancer cells. In this study, cell extracts were analyzed using Ultra High Performance Liquid Chromatography High Resolution Mass Spectrometry (UHPLC-HR-MS). A total of 13,339 signals were identified or annotated using an in-house library and public databases. Supervised and unsupervised multivariate analysis revealed metabolic differences between RT4 cells and ALDH1L1-deficient clones. Glycine (8-fold decrease) and metabolites derived from S-adenosylmethionine utilizing pathways were significantly decreased in the ALDH1L1-deficient clones, compared with RT4 cells. Other changes linked to ALDH1L1 downregulation include decreased levels of amino acids, Krebs cycle intermediates, and ribose-5-phosphate, and increased nicotinic acid. While the ALDH1L1-catalyzed reaction is directly linked to glycine biosynthesis and methyl group flux, its overall effect on cellular metabolism extends beyond immediate metabolic pathways controlled by this enzyme.

  PublisherDOI

• Update of the sideroflexin (SLC56) gene family

  Human Genomics · 2025-06-20 · 4 citations

  reviewOpen access

  The human sideroflexin (SFXN) gene family, also classified as solute carrier family 56 (SLC56), encodes a group of five mitochondrial transmembrane proteins (SFXN1-SFXN5) involved in key aspects of mitochondrial metabolism, cellular homeostasis, and development. SFXNs are highly conserved across eukaryotic species, with evolutionary the origin traced back to the earliest metazoans. Functionally, each of the five family members exhibits distinct functional specialization. Particularly, SFXN1 and SFXN3 facilitate mitochondrial serine transport, supporting one-carbon metabolism. SFXN2 and SFXN4 are implicated in mitochondrial iron regulation, heme biosynthesis, and iron-sulfur cluster assembly. SFXN5, predominantly expressed in the brain, is proposed to regulate citrate metabolism and immune cell functions. Mutations or dysregulation of SFXN genes have been linked to certain human diseases, including congenital sideroblastic anemia, oxidative phosphorylation disorders, neurodegenerative conditions, and cancers. Structurally, SFXNs share conserved transmembrane domains and key motifs critical for substrate transport, mitochondrial iron homeostasis, and overall mitochondrial function. The evolutionary trajectory of the SFXN family-from amino acid transport to functionally specialized roles in higher organisms-highlights their biological and clinical significance. Comparative studies across model organisms reveal both conserved and divergent functions, emphasizing their importance in health and disease. A comprehensive understanding of the SFXN family not only advances fundamental mitochondrial research but also opens avenues for novel therapeutic interventions.

  PublisherOA PDFDOI

• Transgenerational diabetogenic effects of preconception exposure to inorganic arsenic in C57BL/6 mice are associated with dysregulation of DNA methylation and gene expression in G1 and G2 offspring

  Archives of Toxicology · 2025-06-12 · 2 citations

  article
  PublisherDOI

• Aldehyde Dehydrogenases

  Elsevier eBooks · 2025-01-01

  book-chapter
  PublisherDOI

• Abstract 280: ALDH2 knockout dysregulates arginine and proline metabolism in SK-BR-3 breast cancer cells

  Cancer Research · 2025-04-21

  article

  Abstract Aldehyde dehydrogenase 2 (ALDH2) mitigates cellular stress by detoxifying reactive aldehydes produced during alcohol exposure and endogenous metabolic processes. The ALDH2*2 variant, prevalent in East Asian populations, has decreased catalytic activity, which is linked to an increased risk of cancer and other diseases. While the effects of ALDH2 deficiency on cellular stress responses are well documented, the specific metabolic dysregulations arising from this deficiency require further investigation. To explore the impact of ALDH2 deficiency on metabolism and cellular stress in breast cancer, we generated the ALDH2 knockout subline of the SKBR-3 cell line (SKBR-3/ADKO) using CRISPR/Cas9 technology. Our findings indicate that ALDH2 knockout leads to heightened cellular stress, evidenced by elevated levels of 8-OHdG, reactive oxygen species (ROS), and malondialdehyde (MDA). Untargeted metabolomic analysis of SKBR-3 and SKBR-3/ADKO cells using Ultra High Performance Liquid Chromatography/High Resolution Mass Spectrometry assigned a total of 5, 033 metabolites, with 615 metabolites being significantly different (fold change ≥ 2, p-value &amp;lt; 0.05) between the two cell lines. The Mummichog approach has identified six key metabolic pathways altered upon ALDH2 knockout, including: arginine biosynthesis; D-amino acid metabolism; arginine and proline metabolism; alanine, aspartate and glutamate metabolism; pentose and glucuronate interconversions; pantothenate and CoA biosynthesis. The most significantly dysregulated pathway in response to the ALDH2 loss was arginine and proline metabolism, which is an integral pathway to redox homeostasis, ROS production, and cellular stress responses. Our study provides a novel insight into the role of ALDH2 in cancer metabolism, which might have a broader implication for cancer biology. Citation Format: Ming Zhao, Blake R. Rushing, Zhikun Ma, Rachel A. Coble, Amanda B. Parris, Sergey Krupenko, Susan J. Sumner, Xiaohe Yang. ALDH2 knockout dysregulates arginine and proline metabolism in SK-BR-3 breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 280.

  PublisherDOI

Recent grants

• NIH Grant R01DK054388

  NIH · $5.0M · 2018

• Mechanistic and metabolomic underpinnings of ALDH1L1 polymorphisms in the regulation of glycine metabolism

  NIH · $3.4M · 2021–2026

• Regulation of mitochondrial function by folate enzyme ALDH1L2 in health and disease

  NIH · $2.4M · 2019–2025

• NIH Grant R01CA095030

  NIH · $2.5M · 2016

Frequent coauthors

• Natalia I. Krupenko

  David H. Murdock Research Institute

  104 shared

• Susan Sumner

  University of California, Los Angeles

  34 shared

• Jaspreet Sharma

  30 shared

• Natalia Oleinik

  Medical University of South Carolina

  19 shared

• Stephen D. Hursting

  University of North Carolina at Chapel Hill

  17 shared

• Kristi L. Helke

  Medical University of South Carolina

  17 shared

• Blake R. Rushing

  University of North Carolina at Chapel Hill

  17 shared

• Zahra Ashkavand

  Albany Medical Center Hospital

  16 shared

Education

• PhD

  Institute of Bioorganic Chemistry NAS of Belarus

  1987