# CKM

## Overview
The CKM gene encodes the muscle-type creatine kinase (M-CK), a critical enzyme in the phosphagen system that plays a pivotal role in energy metabolism within muscle tissues. This enzyme, categorized as a kinase, facilitates the reversible conversion of phosphocreatine and ADP into creatine and ATP, thereby acting as an energy buffer and ensuring a rapid supply of ATP during muscle contraction and relaxation. The CKM protein is predominantly expressed in skeletal and cardiac muscles, where it is strategically localized to support efficient energy transfer and utilization. Its structural configuration as a homodimer is essential for its enzymatic activity, and it interacts with various molecules and other creatine kinase isoforms to maintain energy homeostasis. Alterations in CKM expression or function have been linked to several clinical conditions, including heart failure and dilated cardiomyopathy, highlighting its significance in muscle physiology and potential as a therapeutic target (Wallimann1992Intracellular; Wallimann2011The; Walker2021Acetylation).

## Structure
The CKM protein, or creatine kinase, M-type, is a crucial enzyme in muscle energy metabolism. Its primary structure consists of a sequence of amino acids forming a polypeptide chain. The secondary structure includes an N-terminal helical domain and a C-terminal α/β domain, connected by a 24-residue linker (Schlattner2018Mitochondrial; Sprenger2021Calmodulin). The tertiary structure is characterized by a conserved fold with a small all-α N-terminal domain and a larger α + β C-terminal domain, featuring an eight-stranded antiparallel β-sheet flanked by α-helices, which contribute to the enzyme's active site (Schlattner2018Mitochondrial).

CKM functions as a homodimer, representing its quaternary structure, with each monomer contributing to the overall enzyme activity (Sprenger2021Calmodulin). The loop regions near the active site, particularly residues 60-70 and 323-332, are important for enzyme regulation and differ between isoforms (Sprenger2021Calmodulin). These regions, along with the amphiphilic helix α12 in the C-terminal region, are potential binding sites for calmodulin, a calcium-sensing protein that activates CK during energy-demanding processes (Sprenger2021Calmodulin). The CKM protein may undergo post-translational modifications such as phosphorylation, which can affect its activity and interactions.

## Function
The CKM gene encodes the muscle-type creatine kinase (M-CK), an enzyme crucial for energy homeostasis in muscle tissues with high and fluctuating energy demands. CKM catalyzes the reversible conversion of phosphocreatine (PCr) and ADP to creatine and ATP, acting as an energy buffer and metabolic regulator. This reaction is essential for maintaining a high ATP/ADP ratio, ensuring efficient ATP utilization during muscle contraction and relaxation (Wallimann1992Intracellular; Wallimann2011The).

CKM is predominantly expressed in skeletal and cardiac muscle cells, where it supports muscle contraction by rapidly regenerating ATP from PCr. It is localized at the myofibrillar M-band, where it is functionally coupled to the myofibrillar, actin-activated Mg2+-ATPase, and is also associated with the sarcoplasmic reticulum for ATP-dependent Ca2+ uptake, crucial for muscle relaxation and contraction cycles (Wallimann1992Intracellular).

The CKM enzyme is also involved in the phosphocreatine circuit, which facilitates the diffusion of ATP and ADP, acting as both a temporal and spatial energy buffer. This system is vital for maintaining energy homeostasis in fast-twitch glycolytic muscles, where a large pool of PCr and a high percentage of cytosolic CK are present (Wallimann1992Intracellular).

## Clinical Significance
Mutations and alterations in the CKM gene, which encodes the muscle-specific isoform of creatine kinase, have been implicated in various diseases and conditions. In heart failure, CKM activity is decreased, leading to reduced ATP delivery to myofibrils and contributing to myocardial energetic dysfunction. This is exacerbated by CKM acetylation, which disrupts dimer formation and reduces enzymatic activity, a process linked to heart failure (Walker2021Acetylation).

In dilated cardiomyopathy (DCM), CKM deficiency results in actin depolymerization and desmin disorganization, contributing to the disease's progression. The transcription factor SRF regulates CKM expression, and its inactivation leads to decreased CKM levels, ATP instability, and oxidative stress, further exacerbating DCM (Diguet2011Muscle).

The CKM gene polymorphism rs4884 has been associated with knee osteoarthritis (OA) risk. The GG genotype and G allele of this variant are linked to a protective effect against knee OA, suggesting a role for CKM in muscle function and joint stability (FernándezTorres2020Ancestral).

The CKM Glu83Gly variant is associated with lower baseline CK levels and reduced CK variability, but not with myalgia, indicating its potential impact on muscle-related conditions (Siddiqui2017CKM).

## Interactions
Creatine kinase, M-type (CKM) is involved in several interactions crucial for its function in energy metabolism. CKM primarily functions as a dimer, and its activity is dependent on the formation of these dimers. The dimeric structure is stabilized by salt bridges between lysine residues and negatively charged residues. Acetylation of lysine residues in CKM can disrupt these salt bridges, leading to destabilization of the dimer interface and increased monomer formation, which reduces CKM activity (Walker2021Acetylation).

CKM interacts with ATP and ADP to facilitate the transfer of phosphate groups, a critical process for energy storage and release in muscle tissues. This interaction is part of the enzyme's role in high-energy phosphoryl transfer between phosphocreatine and ATP, essential for muscle contraction and energy homeostasis (Walker2021Acetylation).

CKM also forms complexes with other creatine kinase isoforms, such as mitochondrial creatine kinase (mtCK), although mtCK shows a different regulatory mechanism and is less affected by acetylation compared to CKM (Walker2021Acetylation). These interactions highlight CKM's role in maintaining energy balance in muscle cells and its potential as a therapeutic target in conditions like heart failure where its function is compromised.


## References


[1. (Wallimann1992Intracellular) T Wallimann, M Wyss, D Brdiczka, K Nicolay, and H M Eppenberger. Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochemical Journal, 281(1):21–40, January 1992. URL: http://dx.doi.org/10.1042/bj2810021, doi:10.1042/bj2810021. This article has 1493 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1042/bj2810021)

[2. (Siddiqui2017CKM) Moneeza Kalhan Siddiqui, Abirami Veluchamy, Cyrielle Maroteau, Roger Tavendale, Fiona Carr, Ewan Pearson, Helen Colhoun, Andrew D. Morris, Jacob George, Alexander Doney, Munir Pirmohamed, Ana Alfirevic, Mia Wadelius, Anke H. Maitland van der Zee, Paul M. Ridker, Daniel I. Chasman, and Colin N.A. Palmer. Ckm glu83gly is associated with blunted creatine kinase variation, but not with myalgia. Circulation: Cardiovascular Genetics, August 2017. URL: http://dx.doi.org/10.1161/circgenetics.117.001737, doi:10.1161/circgenetics.117.001737. This article has 4 citations and is from a peer-reviewed journal.](https://doi.org/10.1161/circgenetics.117.001737)

[3. (Walker2021Acetylation) Matthew A. Walker, Juan Chavez, Outi Villet, Xiaoting Tang, Andrew Keller, James E. Bruce, and Rong Tian. Acetylation of muscle creatine kinase negatively impacts high-energy phosphotransfer in heart failure. JCI Insight, February 2021. URL: http://dx.doi.org/10.1172/jci.insight.144301, doi:10.1172/jci.insight.144301. This article has 15 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1172/jci.insight.144301)

[4. (Schlattner2018Mitochondrial) Uwe Schlattner, Laurence Kay, and Malgorzata Tokarska-Schlattner. Mitochondrial Proteolipid Complexes of Creatine Kinase, pages 365–408. Springer Singapore, 2018. URL: http://dx.doi.org/10.1007/978-981-10-7757-9_13, doi:10.1007/978-981-10-7757-9_13. This article has 27 citations.](https://doi.org/10.1007/978-981-10-7757-9_13)

[5. (Sprenger2021Calmodulin) Janina Sprenger, Anda Trifan, Neal Patel, Ashley Vanderbeck, Jenny Bredfelt, Emad Tajkhorshid, Roger Rowlett, Leila Lo Leggio, Karin S. Åkerfeldt, and Sara Linse. Calmodulin complexes with brain and muscle creatine kinase peptides. Current Research in Structural Biology, 3:121–132, 2021. URL: http://dx.doi.org/10.1016/j.crstbi.2021.05.001, doi:10.1016/j.crstbi.2021.05.001. This article has 5 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.crstbi.2021.05.001)

[6. (Wallimann2011The) Theo Wallimann, Malgorzata Tokarska-Schlattner, and Uwe Schlattner. The creatine kinase system and pleiotropic effects of creatine. Amino Acids, 40(5):1271–1296, March 2011. URL: http://dx.doi.org/10.1007/s00726-011-0877-3, doi:10.1007/s00726-011-0877-3. This article has 530 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s00726-011-0877-3)

[7. (Diguet2011Muscle) Nicolas Diguet, Youssef Mallat, Romain Ladouce, Gilles Clodic, Alexandre Prola, Eva Tritsch, Jocelyne Blanc, Jean-Christophe Larcher, Claude Delcayre, Jane-Lise Samuel, Bertrand Friguet, Gérard Bolbach, Zhenlin Li, and Mathias Mericskay. Muscle creatine kinase deficiency triggers both actin depolymerization and desmin disorganization by advanced glycation end products in dilated cardiomyopathy. Journal of Biological Chemistry, 286(40):35007–35019, October 2011. URL: http://dx.doi.org/10.1074/jbc.M111.252395, doi:10.1074/jbc.m111.252395. This article has 70 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.M111.252395)

[8. (FernándezTorres2020Ancestral) Javier Fernández-Torres, Gabriela Angélica Martínez-Nava, Yessica Zamudio-Cuevas, Olivier Christophe Barbier, Juana Narváez-Morales, and Karina Martínez-Flores. Ancestral contribution of the muscle-specific creatine kinase (ckm) polymorphism rs4884 in the knee osteoarthritis risk: a preliminary study. Clinical Rheumatology, 40(1):279–285, June 2020. URL: http://dx.doi.org/10.1007/s10067-020-05238-6, doi:10.1007/s10067-020-05238-6. This article has 2 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s10067-020-05238-6)