Adenosine kinase 4 (AK4) is a widespread small enzyme that plays a key role in cellular energy metabolism, primarily catalyzing the reversible transfer of phosphoryl groups between adenosine nucleotides (e.g., ATP, ADP, and AMP). The protein maintains cellular energy homeostasis by promoting efficient ATP regeneration. Especially under adverse conditions, it is essential for processes such as cell proliferation, survival and metabolic adaptation.AK4 is located in mitochondria and is involved in processes such as hypoxia response, oxidative stress resistance and tumor progression, and is an important regulator of metabolic reprogramming under pathological conditions. This enzyme was first discovered in the late 20th century. Subsequent studies have revealed its multiple functions beyond energy metabolism, including cell signaling and apoptosis regulation. By analyzing its structure and mechanism of action, scientists have explored its unique substrate specificity and physiological adaptations, providing important clues for the study of nucleotide metabolism and mitochondrial function.
AK4 (adenylate kinase 4) is a medium-sized protein with a molecular weight of approximately 25-27 kDa, the exact value of which may vary slightly depending on species and post-translational modifications.
| Species | Human | Mice | Rats | Cattle | Zebrafish |
| Molecular Weight (kDa) | 25.4 | 25.2 | 25.3 | 25.5 | 25.1 |
| Primary Structural Differences | With a conservative core catalytic and mitochondria positioning signal | Highly homologous to human AK4 | Similar function in energy metabolism | Minor variations were found in the N-terminal region | Adapt to the evolution of the low oxygen reaction characteristics |
The human AK4 protein consists of 223 amino acids and has a typical alpha/beta folded structure of the adenylate kinase family. Its tertiary structure contains a central nucleotide-binding domain responsible for ATP/ADP/AMP transfer. Unlike myoglobin, AK4 does not contain a heme group but contains key catalytic residues (e.g., Arg88, Asp93, and Lys21) that are involved in the phosphoryl group transfer reaction.The secondary structure of AK4 consists mainly of a β-sheet and an α-helix, forming a flexible LID structural domain that opens and closes in response to substrate binding. The protein is mainly localized in mitochondria and regulates nucleotide homeostasis under metabolic stress conditions. Unlike the oxygen-binding function of myoglobin, the core function of AK4 is to maintain cellular energy homeostasis, especially in hypoxic conditions and tumor metabolism, where it plays a key role.
Fig. 1 Withaferin-A blocks metastasis via AK4/ROS/HIF-1α/EMT axis.1
Key structural properties of AK4:
AK4's main function is to participate in the steady state adjust nucleotide metabolism and energy in cells, at the same time it also involves a variety of physiological and pathological processes, including mitochondrial function, stress response and cancer progression.
| Function | Description |
| Nucleotide metabolism | Catalyze the reversible transfer of phosphate groups among ATP, ADP and AMP to maintain the cellular energy balance (e.g., 2ADP ↔ATP + AMP). |
| Energy steady-state regulation | By regulating the level of adenosine monophosphate, it affects the energy supply of mitochondria, especially playing a key role under hypoxia or metabolic stress conditions.. |
| Hypoxic adaptation | Stabilize mitochondrial function in hypoxic environments and support cell survival (possibly related to the tumor microenvironment or ischemic tissues). |
| Oxidative stress response | By regulating the ratio of AMP/ATP, it indirectly affects the antioxidant pathway and reduces the damage of reactive oxygen species (ROS) to cells. |
| Association with cancer progression | Overexpressed in various tumors, it may be involved in tumor metastasis and the development of drug resistance by promoting energy recombination and inhibiting apoptosis. |
Compared with enzymes of the same family (such as AK1/AK2), AK4 has unique affinity for substrates and cellular localization (mainly in mitochondria), reflecting its special role in energy stress and diseases.
1. Zhang, Jie, et al. "AK4 Promotes the Progression of HER2‐Positive Breast Cancer by Facilitating Cell Proliferation and Invasion." Disease Markers 2019.1 (2019): 8186091. https://doi.org/10.1155/2019/8186091
This study revealed that AK4 was significantly highly expressed in HER2-positive breast cancer, and its expression level was significantly correlated with clinicopathological characteristics such as pTNM stage (P=0.017) and lymph node metastasis (P=0.046). It has been confirmed through in vivo and in vitro experiments that AK4 drives the progression of HER2-positive breast cancer by promoting the proliferation, invasion and metastasis of tumor cells, suggesting that AK4 can be a novel therapeutic target for this subtype of breast cancer.
2. Jan, Yi-Hua, et al. "Adenylate kinase 4 modulates oxidative stress and stabilizes HIF-1α to drive lung adenocarcinoma metastasis." Journal of Hematology & Oncology 12 (2019): 1-14. https://pubmed.ncbi.nlm.nih.gov/30696468
This study found through transcription factor analysis that AK4 promotes the EMT process of lung cancer by regulating metabolic genes. Based on the connection map, candidate drugs that can reverse the expression of AK4-mediated genes were screened out. In vivo experiments confirmed that it has a significant therapeutic effect on metastatic lung cancer.
3. Chin, Wei-Yao, et al. "Adenylate kinase 4 promotes inflammatory gene expression via Hif1α and AMPK in macrophages." Frontiers in Immunology 12 (2021): 630318. https://doi.org/10.3389/fimmu.2021.630318
This study revealed that adenosine monophosphate kinase 4 (Ak4) is highly expressed specifically in M1-type macrophages. It regulates the expression of inflammatory genes (Il1b, Il6, Tnfa, etc.) by inhibiting AMPK activity and forming a positive feedback loop with Hif1α, while reducing ATP production, ROS generation and glycolytic capacity. Thus, a key connection is established between the energy metabolism and inflammatory response of macrophages, but it does not affect the M1/M2 polarization process.
4. Jan, Yi-Hua, et al. "A co-expressed gene status of adenylate kinase 1/4 reveals prognostic gene signature associated with prognosis and sensitivity to EGFR targeted therapy in lung adenocarcinoma." Scientific reports 9.1 (2019): 12329. https://www.nature.com/articles/s41598-019-48243-9
This study through the system analysis, found that AK4 over expression in lung adenocarcinoma is associated with poor prognosis in patients with significant (P = 0.001), whereas AK1 associated with good prognosis (P = 0.009), and confirmed that AK4 promote tumor progression by regulating the EGFR protein expression, prompt targeted AK4 - AK1 signaling pathways may provide a new strategy for the treatment of patients with lung adenocarcinoma.
5. Fujisawa, Koichi, et al. "Modulation of anti-cancer drug sensitivity through the regulation of mitochondrial activity by adenylate kinase 4." Journal of Experimental & Clinical Cancer Research 35 (2016): 1-15. https://link.springer.com/article/10.1186/s13046-016-0322-2
This study reveals that mitochondrial adenylate kinase 4 (AK4) is involved in the malignant transformation and drug resistance formation of cancer cells by regulating ATP metabolism, oxidative stress response and mitochondrial function. Its expression level is significantly correlated with tumor progression. However, the controversy over its classical enzyme activity remains to be resolved, suggesting that AK4 may become a new target for cancer treatment.
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