HK1

What is HK1 protein?

HK1 (hexokinase 1) gene is a protein coding gene which situated on the chromosome 10 at locus 10q22. Hexokinase 1 protein, commonly abbreviated as HK1, is an enzyme that plays a crucial role in cellular metabolism. It is involved in the first step of glycolysis, where it catalyzes the conversion of glucose to glucose-6-phosphate (G6P) by phosphorylating glucose using ATP as the phosphate donor. This reaction is essential for glucose to enter the glycolytic pathway and be further metabolized to produce energy in the form of ATP. There are various isoforms and related proteins of hexokinase, including a recently discovered protein with hexokinase activity, known as Hexokinase domain-containing protein-1 (HKDC1). The HK1 protein is consisted of 917 amino acids and its molecular mass is approximately 102.5 kDa.

What is the function of HK1 protein?

HK1 catalyzes the first step of glycolysis, which is the phosphorylation of glucose to glucose-6-phosphate (G6P). This step is essential because it commits glucose to the glycolytic pathway. HK1 is involved in glucose sensing in cells, which is important for maintaining glucose homeostasis. HK1 is often bound to the outer mitochondrial membrane, which allows it to have access to ATP produced by the mitochondria and to interact with other metabolic enzymes and pathways. HK1 overexpression can protect cells from apoptosis (programmed cell death) by maintaining high levels of G6P, which can inhibit certain apoptotic pathways.

HK1 Related Signaling Pathway

HK1 catalyzes the first step of glycolysis, converting glucose to glucose-6-phosphate (G6P), which is a critical step in cellular energy production. The product of HK1, G6P, can enter the pentose phosphate pathway to generate NADPH and ribose-5-phosphate, which are important for fatty acid synthesis and nucleotide synthesis, respectively. Recent studies have shown that HK1 can promote glycolysis in immune cells, which is important for their function during inflammation. HK1's activity in glycolysis supports cell proliferation and survival, making it a potential target for cancer therapy.

Fig1. Mechanism for the protective effects of PHL against ISO-induced myocardial fibrosis (MF). (Yuling Zhang, 2023)

HK1 Related Diseases

HK1 is often overexpressed in various types of cancer, contributing to the Warburg effect, which is the increased glycolysis in cancer cells even in the presence of oxygen. It supports the high energy and biosynthetic demands of rapidly proliferating cancer cells. A deficiency in HK1 can lead to a form of hemolytic anemia, which is characterized by the destruction of red blood cells and the release of hemoglobin into the plasma. HK1 is listed in the NIH Genetic Testing Registry as being associated with this type of inherited neuropathy. HK1 may play a role in the activation of the NLRP3 inflammasome, which is involved in inflammatory responses, and could be related to conditions with an inflammatory component.

Bioapplications of HK1

HK1 has been shown to interact with TERT, the catalytic component of telomerase, potentially influencing cell aging and telomere length in lung adenocarcinoma cells. HK1 or its isoforms, such as HK2, are being explored as diagnostic markers for certain cancers. For instance, HK2 has been studied for its potential as a broad-spectrum tumor marker. HK1, along with HK2, has been identified as a cell-intrinsic metabolic checkpoint that may restrict cellular processes, including responses to certain immune signals.

Case Study 1: Minlan Yang, 2023

Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), may increase the risk of cancer development and a poor cancer prognosis. TAMs of the M2 phenotype, together with the intermittent hypoxic environment within the tumor, drive tumor aggressiveness. However, the mechanism of TAMs in IH remains unclear. In this study, IH induced the recruitment of macrophages, and IH-induced M2-like TAMs promoted glycolysis in laryngeal cancer cells through hexokinase 1. The hexokinase inhibitor 2-deoxy-D-glucose and HK1 shRNA were applied to verify this finding, confirming that M2-like TAMs enhanced glycolysis in laryngeal cancer cells through HK1 under intermittent hypoxic conditions. Comprehensive RNA-seq analysis disclosed a marked elevation in the expression levels of the transcription factor ZBTB10, while evaluation of a laryngeal cancer patient tissue microarray demonstrated a positive correlation between ZBTB10 and HK1 expression in laryngeal carcinoma. Knockdown of ZBTB10 decreased HK1 expression, and overexpression of ZBTB10 increased HK1 expression in both laryngeal cancer cells and 293T cells. The luciferase reporter assay and Chromatin immunoprecipitation assay confirmed that ZBTB10 directly bound to the promoter region of HK1 and regulated the transcriptional activity of HK1.

Fig1. Representative Western blot images showing HK1 protein levels.

Fig2. Luciferase activity of HK1 in ZBTB10 knockout 293T cells.

Case Study 2: Caroline R Amendola, 2019

The most frequently mutated oncogene in cancer is KRAS, which uses alternative fourth exons to generate two gene products (KRAS4A and KRAS4B) that differ only in their C-terminal membrane-targeting region. Because oncogenic mutations occur in exons 2 or 3, two constitutively active KRAS proteins-each capable of transforming cells-are encoded when KRAS is activated by mutation. No functional distinctions among the splice variants have so far been established. Oncogenic KRAS alters the metabolism of tumour cells in several ways, including increased glucose uptake and glycolysis even in the presence of abundant oxygen (the Warburg effect). Whereas these metabolic effects of oncogenic KRAS have been explained by transcriptional upregulation of glucose transporters and glycolytic enzymes, it is not known whether there is direct regulation of metabolic enzymes. Here the researchers report a direct, GTP-dependent interaction between KRAS4A and hexokinase 1 (HK1) that alters the activity of the kinase, and thereby establish that HK1 is an effector of KRAS4A. This interaction is unique to KRAS4A because the palmitoylation-depalmitoylation cycle of this RAS isoform enables colocalization with HK1 on the outer mitochondrial membrane.

Fig3. Co-immunoprecipitation of endogenous HK1 with endogenous KRAS4A.

Fig4. Activity of recombinant full-length HK1.

HK1 has several biochemical functions, for example, ATP binding,fructokinase activity,glucokinase activity. Some of the functions are cooperated with other proteins, some of the functions could acted by HK1 itself. We selected most functions HK1 had, and list some proteins which have the same functions with HK1. You can find most of the proteins on our site.

HK1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with HK1 here. Most of them are supplied by our site. Hope this information will be useful for your research of HK1.

ATF2;GBAS;VDAC1;MAX;ATG101;ENO2;SCMH1;MYC;ICT1;LRRK2