# HKDC1

## Overview
Hexokinase domain containing 1 (HKDC1) is a gene that encodes a protein involved in glucose metabolism, functioning as a novel member of the hexokinase family. The HKDC1 protein, characterized by its hexokinase domain, plays a role in the phosphorylation of glucose, a critical step in glycolysis, although it exhibits lower enzymatic activity compared to other hexokinases. It is broadly expressed in various human tissues, including the liver and kidney, and is associated with mitochondrial localization, interacting with proteins such as VDAC1 and VDAC2. HKDC1 is implicated in several physiological and pathological processes, including glucose homeostasis, gestational diabetes, and cancer progression, particularly in hepatocellular carcinoma and pancreatic adenocarcinoma. Its expression and activity are crucial for maintaining cellular metabolism and have been linked to metabolic phenotypes and disease states (Khan2021The; Ludvik2016HKDC1; Pusec2018Hepatic).

## Structure
The HKDC1 protein is characterized by the presence of a hexokinase domain, which is essential for its role in glucose metabolism. This domain typically includes an ATP-binding site and a glucose-binding site, which are crucial for its enzymatic activity. The protein's structure may be influenced by post-translational modifications such as phosphorylation, which can regulate its activity. HKDC1 can exist in different isoforms due to alternative splicing, potentially affecting its function and localization. These isoforms may exhibit variations in their structural domains, which could influence their interaction with other cellular components and their overall metabolic roles. The conserved structure of hexokinases, including HKDC1, generally supports their function in catalyzing the phosphorylation of glucose, a key step in glycolysis. The specific structural details of HKDC1, such as its secondary, tertiary, and quaternary structures, are not detailed in the available context, but the presence of the hexokinase domain suggests a level of structural conservation typical of this enzyme family.

## Function
HKDC1 (hexokinase domain containing 1) is a gene that encodes a protein involved in glucose metabolism, functioning as a novel hexokinase. It is considered a fifth hexokinase, distinct from the previously known four hexokinases in humans, and is involved in whole-body glucose homeostasis (Ludvik2016HKDC1). HKDC1 is broadly expressed in human tissues, including the liver, colon, and kidney, but is absent from muscle and adipose tissue (Ludvik2016HKDC1). The protein is involved in phosphorylating glucose to produce glucose-6-phosphate, a crucial step in glycolysis, although it has reduced activity compared to other hexokinases like HK1 and GCK (Pusec2018Hepatic).

In cellular biology, HKDC1 is associated with mitochondria, similar to HK1 and HK2, and interacts with outer mitochondrial membrane proteins VDAC1 and VDAC2, suggesting a role in mitochondrial localization (Pusec2018Hepatic). Despite its low enzymatic activity, HKDC1 contributes to cellular hexokinase activity, with studies indicating that about half of the hexokinase activity in HepG2 cells is due to HKDC1 (Guo2015Coordinated). The gene plays a significant role in regulating glucose levels and hexokinase activity, potentially impacting metabolic phenotypes such as diabetes (Guo2015Coordinated). HKDC1's expression is crucial during pregnancy, affecting glucose tolerance and energy storage (Ludvik2016HKDC1).

## Clinical Significance
Mutations and alterations in the HKDC1 gene have been linked to several diseases and conditions. A homozygous variant in HKDC1, specifically c.173C>T, p.T58M, has been associated with autosomal-recessive retinitis pigmentosa (RP) in two families. This variant results in a partial loss of hexokinase activity, suggesting a negative impact on the protein's function in the retina (Zhang2018Wholeexome).

In the context of glucose metabolism, HKDC1 plays a significant role in gestational diabetes mellitus (GDM). Variants in HKDC1 have been associated with altered glucose levels during pregnancy, particularly affecting maternal 2-hour glucose levels. These genetic variations can lead to reduced expression of HKDC1, contributing to gestational hyperglycemia (Guo2015Coordinated; Zapater2021The).

HKDC1 is also implicated in cancer. Its upregulation has been observed in hepatocarcinoma (HCC) and pancreatic adenocarcinoma (PAAD), where it is associated with poor prognosis and aggressive tumor behavior. In HCC, high HKDC1 expression correlates with increased cell proliferation and migration, while in PAAD, it enhances glycolysis and immune evasion, potentially impacting treatment outcomes (Pang2024HKDC1; Zhang2016High).

## Interactions
HKDC1 interacts with several proteins, playing a crucial role in cellular metabolism and cancer progression. In hepatocellular carcinoma (HCC), HKDC1 is essential for maintaining mitochondrial function and cellular metabolism. It localizes to the mitochondria and interacts with mitochondrial proteins such as voltage-dependent anion channel (VDAC), which is necessary for its function in HCC metabolism, proliferation, and survival (Khan2021The; Khan2022The). The interaction with VDAC is mediated by an N-terminus targeting sequence, and experiments have shown that a truncated version of HKDC1 lacking this sequence cannot rescue the effects of HKDC1 ablation, highlighting the importance of this interaction (Khan2021The).

In extranodal natural killer/T-cell lymphoma (ENKTL), HKDC1's C-terminal region, particularly the last eight amino acids, is crucial for its interaction with VDAC1. This interaction is significant for regulating tumor growth and apoptosis in ENKTL cells (Chen2020HKDC1). HKDC1 also facilitates immune evasion in HCC by interacting with cytosolic STAT1 and presenting it to IFNGR1 on the plasma membrane, which enhances PD-L1 expression and contributes to immune checkpoint blockade therapy resistance (Zhang2024HKDC1).


## References


[1. (Pang2024HKDC1) Qiang Pang, Shansong Huang, and Jiaqing Cao. Hkdc1 enhances the proliferation, migration and glycolysis of pancreatic adenocarcinoma and is linked to immune infiltration. Journal of Cancer, 15(7):1983–1993, 2024. URL: http://dx.doi.org/10.7150/jca.92823, doi:10.7150/jca.92823. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.7150/jca.92823)

[2. (Chen2020HKDC1) Qi Chen, Jia Feng, Jinhu Wu, Zhendong Yu, Wei Zhang, Yonggang Chen, Paul Yao, and Hongyu Zhang. Hkdc1 c-terminal based peptides inhibit extranodal natural killer/t-cell lymphoma by modulation of mitochondrial function and ebv suppression. Leukemia, 34(10):2736–2748, March 2020. URL: http://dx.doi.org/10.1038/s41375-020-0801-5, doi:10.1038/s41375-020-0801-5. This article has 21 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41375-020-0801-5)

[3. (Zhang2016High) Zijian Zhang, Shanzhou Huang, Huanyu Wang, Jian Wu, Dong Chen, Baogang Peng, and Qi Zhou. High expression of hexokinase domain containing 1 is associated with poor prognosis and aggressive phenotype in hepatocarcinoma. Biochemical and Biophysical Research Communications, 474(4):673–679, June 2016. URL: http://dx.doi.org/10.1016/j.bbrc.2016.05.007, doi:10.1016/j.bbrc.2016.05.007. This article has 48 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.bbrc.2016.05.007)

[4. (Zapater2021The) Joseph L. Zapater, Kristen R. Lednovich, and Brian T. Layden. The role of hexokinase domain containing protein-1 in glucose regulation during pregnancy. Current Diabetes Reports, July 2021. URL: http://dx.doi.org/10.1007/s11892-021-01394-4, doi:10.1007/s11892-021-01394-4. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s11892-021-01394-4)

5. (Khan2021The) The hexokinase “HKDC1” interaction with the mitochondria is essential for hepatocellular carcinoma progression. This article has 0 citations.

[6. (Zhang2024HKDC1) Yi Zhang, Mingjie Wang, Ling Ye, Shengqi Shen, Yuxi Zhang, Xiaoyu Qian, Tong Zhang, Mengqiu Yuan, Zijian Ye, Jin Cai, Xiang Meng, Shiqiao Qiu, Shengzhi Liu, Rui Liu, Weidong Jia, Xianzhu Yang, Huafeng Zhang, Xiuying Zhong, and Ping Gao. Hkdc1 promotes tumor immune evasion in hepatocellular carcinoma by coupling cytoskeleton to stat1 activation and pd-l1 expression. Nature Communications, February 2024. URL: http://dx.doi.org/10.1038/s41467-024-45712-2, doi:10.1038/s41467-024-45712-2. This article has 0 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-024-45712-2)

[7. (Khan2022The) Md. Wasim Khan, Alexander R. Terry, Medha Priyadarshini, Vladimir Ilievski, Zeenat Farooq, Grace Guzman, Jose Cordoba-Chacon, Issam Ben-Sahra, Barton Wicksteed, and Brian T. Layden. The hexokinase “hkdc1” interaction with the mitochondria is essential for liver cancer progression. Cell Death & Disease, July 2022. URL: http://dx.doi.org/10.1038/s41419-022-04999-z, doi:10.1038/s41419-022-04999-z. This article has 16 citations.](https://doi.org/10.1038/s41419-022-04999-z)

[8. (Zhang2018Wholeexome) Lin Zhang, Zixi Sun, Peiquan Zhao, Lulin Huang, Mingchu Xu, Yeming Yang, Xue Chen, Fang Lu, Xiang Zhang, Hui Wang, Shanshan Zhang, Wenjing Liu, Zhilin Jiang, Shi Ma, Rui Chen, Chen Zhao, Zhenglin Yang, Ruifang Sui, and Xianjun Zhu. Whole-exome sequencing revealed hkdc1 as a candidate gene associated with autosomal-recessive retinitis pigmentosa. Human Molecular Genetics, September 2018. URL: http://dx.doi.org/10.1093/hmg/ddy281, doi:10.1093/hmg/ddy281. This article has 3 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1093/hmg/ddy281)

[9. (Ludvik2016HKDC1) Anton E. Ludvik, Carolina M. Pusec, Medha Priyadarshini, Anthony R. Angueira, Cong Guo, Amy Lo, Korri S. Hershenhouse, Guang-Yu Yang, Xianzhong Ding, Timothy E. Reddy, William L. Lowe, and Brian T. Layden. Hkdc1 is a novel hexokinase involved in whole-body glucose use. Endocrinology, 157(9):3452–3461, July 2016. URL: http://dx.doi.org/10.1210/en.2016-1288, doi:10.1210/en.2016-1288. This article has 59 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1210/en.2016-1288)

[10. (Pusec2018Hepatic) Carolina M Pusec, Adam De Jesus, Md Wasim Khan, Alexander R Terry, Anton E Ludvik, Kai Xu, Nicholas Giancola, Haaris Pervaiz, Emily Daviau Smith, Xianzhong Ding, Stephen Harrison, Navdeep S Chandel, Thomas C Becker, Nissim Hay, Hossein Ardehali, Jose Cordoba-Chacon, and Brian T Layden. Hepatic hkdc1 expression contributes to liver metabolism. Endocrinology, 160(2):313–330, December 2018. URL: http://dx.doi.org/10.1210/en.2018-00887, doi:10.1210/en.2018-00887. This article has 42 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1210/en.2018-00887)

[11. (Guo2015Coordinated) Cong Guo, Anton E. Ludvik, Michelle E. Arlotto, M. Geoffrey Hayes, Loren L. Armstrong, Denise M. Scholtens, Christopher D. Brown, Christopher B. Newgard, Thomas C. Becker, Brian T. Layden, William L. Lowe, and Timothy E. Reddy. Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase hkdc1. Nature Communications, February 2015. URL: http://dx.doi.org/10.1038/ncomms7069, doi:10.1038/ncomms7069. This article has 77 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/ncomms7069)