Metabolism: the mysteries of orphan enzymes

Prof. Jakub Drożak with collaborators

Metabolism is a set of chemical reactions that power the life of every cell. Enzymes, the proteins catalyzing these processes, play a key role. Among them are orphan enzymes, whose functions and coding genes remain largely unknown. Research into their roles has the potential to revolutionize our understanding of metabolic processes. 

The team’s research focuses on the biochemical and physiological characterization of human orphan enzymes. These enzymes represent a unique group of proteins whose molecular identity and regulation remain enigmatic. One of the team’s groundbreaking discoveries was identifying the SETD3 enzyme, capable of methylating histidine residues in proteins. This process affects the functioning of the cellular cytoskeleton and may be associated with the initiation of carcinogenesis.

The role of the BDH2 enzyme, which neutralizes toxic 4-oxo-L-proline to protect cells from its harmful effects, and the involvement of HSD17B14 in the initial stage of L-fucose sugar degradation have also been investigated. These studies shed light on previously unknown mechanisms of metabolite degradation.

The team collaborates with the Institute of Mother and Child to analyze defective gene variants in Polish patients with rare metabolic diseases. Notably, they demonstrated the impact of mutations in TRPV6 calcium channels on the development of chronic pancreatitis in children.

MODERN APPLICATIONS:

Knowledge about orphan enzymes enables the development of targeted therapies for metabolic and cancer-related diseases and supports the diagnosis of rare conditions in children. It may also lead to the design of drugs that modify metabolic pathways for therapeutic purposes.

FIGURE CAPTIONS:

Top: Comparison of NAD(P)H coenzyme binding in the active center of the human enzyme HSD17B14 and bacterial L-fucose dehydrogenase.

Bottom: Spatial structure of the human TRPV6 protein, functioning as a cellular calcium ion channel.

RELATED PUBLICATIONS:

1. Witecka A, Kazak V, Kwiatkowski S, Kiersztan A, Jagielski AK, Kozminski W, Augustyniak R, Drozak J. (2024) Hydroxysteroid 17-β dehydrogenase 14 (HSD17B14) is an L-fucose dehydrogenase, the initial enzyme of the L-fucose degradation pathway. J Biol Chem 300:107501. doi: 1016/j.jbc.2024.107501
2. Kwiatkowski S, Bozko M, Zarod M, Witecka A, Kocdemir K, Jagielski AK, Drozak J. (2022) Recharacterization of the mammalian cytosolic type 2 (R)-β-hydroxybutyrate dehydrogenase as 4-oxo-l-proline reductase (EC 1.1.1.104). J Biol Chem 298(3):101708. doi: 1016/j.jbc.2022.101708
3. Witecka A, Kwiatkowski S, Ishikawa T, Drozak J. (2021) The Structure, Activity, and Function of the SETD3 Protein Histidine Methyltransferase. Life (Basel). 11:1040. doi: 3390/life11101040
4. Oracz G et al. (2021) Loss of function TRPV6 variants are associated with chronic pancreatitis in nonalcoholic early-onset Polish and German patients. Pancreatology 21:1434-1442. doi: 1016/j.pan.2021.09.005
5. Kwiatkowski S, Drozak J. (2020) Protein Histidine Methylation. Curr Protein Pept Sci 21:675-689. doi: 2174/1389203721666200318161330
6. Guo Q, Liao S, Kwiatkowski S, Tomaka W, Yu H, Wu G, Tu X, Min J, Drozak J, Xu C. (2019) Structural insights into SETD3-mediated histidine methylation on β-actin. Elife. 8:e43676. doi: 7554/eLife.43676
7. Kwiatkowski S et al. (2018) SETD3 protein is the actin-specific histidine N-methyltransferase. Elife. 7:e37921. doi: 7554/eLife.37921

RELATED PROJECTS:

1. Biochemical characterization of human SETD3 methyltransferase – Opus grant, National Science Centre (NCN), 2018-2023, PI: J. Drożak
2. Identification of novel genetic variants associated with risk of chronic pancreatitis by whole exome sequencing.– Opus grant, National Science Centre (NCN), 2016-2021, PI: A. Rygiel
3. Molecular and biochemical characterization of eukaryotic C9orf41 protein – Opus grant, National Science Centre (NCN), 2014-2016, PI: J. Drożak