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PubMed1977

Localization of creatine kinase isoenzymes in myofibrils. II. Chicken heart muscle.

Chicken heart muscle contains almost exclusively the BB isoenzyme of creatine kinase (CK), its myofibrils, moreover, lack an M-line. This tissue thus provides an interesting contrast to skeletal muscle, in which some of the MM-CK present as predominant CK isoenzyme is bound at the myofibrillar M-line. Approx. 2% of the total CK activity in a chicken heart homogenate remains bound to the myofibrillar fraction after repeated washing cycles; both the fraction and the absolute amount of CK bound are about threefold lower than in skeletal muscle. Almost all of the bound enzyme is located within the Z-line region of each sarcomere, as revealed by indirect fluorescent-antibody staining with antiserum against purified chicken BB-CK. After incubation with exogenous purified MM-CK, positive immunofluorescent staining for M-type CK at the H-region of heart myofibrils was observed, along with weaker fluorescence in the Z-line region. Chicken heart myofibrils may thus possess binding sites for both M and B forms of CK.

Animals↗

PubMed1994

Hybridization of matrix-bound MM-creatine kinase with BB-creatine kinase and arginine kinase.

Dimeric rabbit muscle creatine kinase (MM-CK) was bound to CNBr-activated Sepharose 4B by one of its subunits (MM-CKA). Treatment of MM-CKA with guanidine hydrochloride released the unbound subunit to yield the matrix-bound monomer (M-CKB). M-CKB recombined with dissociated MM-CK soluble subunits to reconstitute a matrix-bound dimer (MM-CKC). M-CKB also associated with dissociated subunits of BB-CK from crude extracts of rabbit brain and of arginine kinase from sea cucumber muscle (MM-AK) to form the matrix-bound heterohybrids MB-CKC and M-CK/M-AKC, respectively. Guanidine hydrochloride gradient elution studies showed that MM-CKA, MM-CKC and MB-CKC were all dissociated at the same concentration of the denaturant (0.96 M), while the M-CK/M-AKC heterohybrid was less stable, dissociating at 0.5 M. The specific interaction between subunits of echinoderm and mammalian phosphagen kinases to form a hybrid enzyme of dual substrate specificity supports the view that these enzymes had a common evolutionary origin.

Animals↗

PubMed1995

Study of the heterogeneity of creatine kinase-MM isoforms using western blotting.

OBJECTIVE: To study creatine kinase isoform variants in muscle (skeletal and myocardial) damage using a Western blotting procedure. DESIGN AND METHODS: The study comprised of 16 patients admitted with chest pain, 14 patients with skeletal muscle damage, and 4 healthy individuals. The creatine kinase-MM (CK-MM) isoforms were separated by isoelectric focusing and detected by electrophoretic transfer to a nitrocellulose membrane and immunoblotting. Binding of the first monoclonal mouse anti-human CK-MM antibody was detected by either a horseradish peroxidase or alkaline phosphatase anti-mouse immunoglobulin conjugate. RESULTS: Three major variants of CK-MM (MM3 pl = 6.8; MM2 pl = 6.4; MM1 pl = 6.2) were detected. Minor sub-bands were detected in 4/16 and 3/14 patients with acute myocardial infarction (AMI) and skeletal muscle damage, respectively. The tissue form (MM0 pl = 7.14) was visible in 6/16 patients with AMI and 4/14 patients with skeletal muscle damage. The appearance of minor variants was therefore of limited diagnostic value in discriminating between patients with and without AMI. Immunoblotting confirms the parallel increase in mass and activity of CK-MM isoforms, thus confirming measurement of isoform activity as an early marker of AMI or reperfusion following thrombolytic therapy. CONCLUSIONS: Study of isoform patterns gives more information concerning AMI and skeletal muscle trauma than is currently available from CK isoenzyme analysis. However, because CK-MM is also released in skeletal muscle damage, in such instances more discriminant markers of AMI are needed.

Adult↗

PubMed1994

Cardiac injury associated with neurogenic pulmonary edema following subarachnoid hemorrhage.

OBJECTIVE: To describe the clinical features of cardiac injury associated with neurogenic pulmonary edema (NPE) in patients with acute subarachnoid hemorrhage (SAH). BACKGROUND: NPE is generally viewed as a form of noncardiogenic pulmonary edema related to massive sympathetic discharge. METHODS: Case series. RESULTS: We found echocardiographic evidence of reduced global and segmental left ventricular (LV) systolic function in five women (mean age, 44; range, 36 to 57) with SAH and NPE. None had a history of heart disease. Four patients were Hunt/Hess grade III and one was grade IV. All five patients experienced (1) sudden hypotension (systolic blood pressure < 110 mm Hg) following initially elevated blood pressures, (2) transient lactic acidosis, (3) borderline (2 to 4%) creatine kinase MB elevations, and (4) varied acute (< 24 hours) electrocardiographic changes followed by widespread and persistent T wave inversions. Pulmonary artery wedge pressures were normal in 3/3 patients at the onset of pulmonary edema but reached high levels (> 16 mm Hg) in all four patients studied beyond this period. Reduced cardiac output and LV stroke volume were identified in three patients; the fourth patient demonstrated normal values on high doses of intravenous pressors. Cerebral infarction due to vasospasm occurred in four patients and resulted in two deaths. Follow-up echocardiography performed 2 to 6 weeks after SAH revealed normal LV function in all three survivors. CONCLUSIONS: A reversible form of cardiac injury may occur in patients with NPE following SAH and is associated with characteristic clinical findings. Impaired LV hemodynamic performance in this setting may contribute to cardiovascular instability, pulmonary edema formation, and complications from cerebral ischemia.

Adult↗

PubMed1983

Creatine kinase variants. Report on the workshop conference of the German Society for Clinical Chemistry held on September 19 to 21, 1982 in Tübingen, FRG.

It was the aim of the workshop to summarize present knowledge of the variant creatine kinases in human blood. Discussion was centered on the nature, measurement, and clinical significance of these variants. On the basis of the presented results, the different creatine kinase variants can be classified as follows: Normal size variants (80000 Daltons). These originate from postsynthetic modifications of the three dimeric isoenzymes creatine kinase-MM, MB or BB. The M subunit can be transformed by a serum constituent and these modifications result in at least three different creatine kinase-MM and two creatine kinase-MB variants, which still show catalytic activity. The mechanism of the postsynthetic alterations of creatine kinase-BB seems to be more complex: In vitro incubation of this isoenzyme even in a non-serum matrix changes its electrophoretic mobility and decreases activity. In vivo there is evidence that on the one hand intact creatine kinase-BB molecules are directly removed from the circulation. On the other hand, however, inactive creatine kinase-BB-protein is reported to occur in serum. Variants with higher molecular weights (greater than 200000 Daltons). These are termed macro creatine kinases. Macro creatine kinase type 1 comprises the immunoglobulin-bound creatine kinase isoenzymes. Of these immune complexes, IgG-linked creatine kinase-BB is well known and has been described in detail, whereas the occurrence of creatine kinase-MM-containing macro creatine kinases is still questionable. Macro creatine kinase type 1 is found in the blood of about 2% of all hospitalized patients. It occurs mainly in elderly women, but it is not known whether it has any special clinical significance. Macro creatine kinase type 2 is the term for an oligomeric form of mitochondrial creatine kinase released after breakdown of mitochondria in liver, heart and some tumours. After treatment with urea this oligomeric form is converted into a normal sized, dimeric creatine kinase-MiMi. Macro creatine kinase type 2 is found exclusively in seriously ill patients, and may occur in more than 3% of all hospitalized patients. This classification of the creatine kinase variants seems logical, since it takes into account the nature of the creatine kinase variants, and it permits the classification of all atypical creatine kinases described in the literature. As quantification and differentiation now become possible, further experimental and clinical investigations should provide the information necessary for a better understanding of the physiology and pathobiochemistry of these multiple forms of creatine kinase.

Creatine Kinase↗

PubMed1977

Brain isoenzyme of creatine kinase. III. Active and inactive forms in dystrophic muscle of vitamin E-dificient rabbit.

Rabbits were fed a vitamin E-deficient diet for 7 weeks. Control rabbits, paired for weight, were pair-fed an identical diet supplemented with vitamin E. After 3 weeks the expermental animals showed a rise in serum creatin kinase activity which was attributable to the muscle isoenzyme (MM). No rise in creatine kinase activity or appearance of MM was noted in the serum of the control rabbits. Total creatine kinase activity and MM activity were reduced in the gastrocnemii of the experimental animals while the activities of the brain (BB) and hybird (MB) isoenzymes were increased. The specific activity of BB based on immunochemically determined BB protein was not different from normal in either the experimental or control group. Activation of pre-existing inactive BB is probably not the explanation for increased BB activity in the gastroncnemii of the experimental group.

Animals↗

PubMed1997

Purification and characterization of human sarcomeric mitochondrial creatine kinase.

In order to set the basis for detailed clinical investigations, mitochondrial creatine kinase (Mi-CK) was purified to homogeneity from human cardiac muscle. Biophysical characterization by SDS-PAGE, gel permeation chromatography and by electron microscopy of negatively stained single molecules demonstrated that, similar to other vertebrate Mi-CKs, human sarcomeric Mi-CK occurs in two different oligomeric forms, dimers and octamers, that are readily interconvertible. The apparent MTs of Mi-CK protomers, dimers and octamers were 43,600 +/- 800, 79,700 +/- 800 and 371,000 +/- 3000, respectively. In addition, isoelectric focussing proved to be a suitable technique for routinely distinguishing Mi-CK from cytosolic MM-CK and gave pl values of 8.30 +/- 0.04 and 7.44 +/- 0.04 for octameric and dimeric human sarcomeric Mi-CK. Circumstantial evidence suggests that both the highly symmetrical structure and the high pI value of Mi-CK octamers are crucial determinants for the physiological functions of this enzyme.

Creatine Kinase↗

PubMed1989

Kinetic properties of the octameric and dimeric forms of mitochondrial creatine kinase and physiological role of the enzyme.

It has been found that at pH 7.4 and 2 mg/ml protein, bovine heart mitochondrial creatine kinase (CKm) contains less than 10% of the dimer. The constant for the CKm octamer dissociation into dimers, Kd, in the presence of substrates forming an analog of the complex of the transient state was found to be equal to 4.9 10(-17) M3. Using this value, the experimental conditions were chosen so as to achieve a practically complete dissociation of the octamer into dimers. Evidence has been obtained suggesting that the octamer does not dissociate into dimers during the time course of the kinetic experiments; the corresponding kinetic parameters of the CKm octamer and dimer are as follows: KMgATPm = 82 microM and 42 microM; KCrm = 8.1 mM and 3.4 mM; Vf = 61 and 60 micrograms-equiv. H+ min-1 mg-1; KMgADPm = 43 microM and 17 microM, KCPm = 0.68 mM and 0.23 mM; Vr = 162 and 111 micrograms-equiv. H+ min-1 mg-1. The experimental and calculated data shed additional light on the physiological role of CKm.

Animals↗

PubMed1973

Creatine phosphokinase activity in rabbit alveolar macrophages.

An enzyme is present in extracts of rabbit alveolar macrophage which can catalyze the reaction of creatine phosphate with adenosine diphosphate to form adenosine triphosphate and creatine. The enzyme is moderately activated by reduced glutathione, has a pH optimum between pH 6.5 and 7.0, and shows an absolute requirement for Mg(2+). The K(m) for creatine phosphate is approximately 3.6 mm while the K(m) for adenosine diphosphate is about 1.1 mm. The enzyme may play a role in the energy balance of the cell by creating a reserve of energy in the form of creatine phosphate.

Animals↗

PubMed1997

Phosphoglycerate mutase, 2,3-bisphosphoglycerate phosphatase and creatine kinase activity and isoenzymes in human brain tumours.

The distribution of phosphoglycerate mutase (EC 5.4.2.1, PGM), 2,3-bisphosphoglycerate phosphatase (EC 3.1.3.13, BPGP) and creatine kinase (EC 2.7.3.2, CK) activity and isoenzymes in various regions of adult human brain and in brain tumours (astrocytomas, anaplastic astrocytomas, glioblastomas and meningiomas) has been determined using electrophoresis. PGM and cytosolic CK exist in mammalian tissues as three isoenzymes that result from the homodimeric and heterodimeric combinations of two subunits [types M (muscle) and B (brain)] coded by separated genes. In addition, a dimeric form and an octameric form of mitochondrial CK exist in mammals. Type BB-PGM was the major PGM isoenzyme found in normal brain, although type MB-PGM and type MM-PGM were also detected. All brain tumours possessed lower PGM activity than normal brain, and meningiomas showed higher BPGP activity. In astrocytic tumours, the proportion of type MB- and type MM-PGM decreased, and in meningiomas these isoenzymes were not detected. Type BB-CK and mitochondrial CK were the only CK isoenzymes detected in normal brain. Astrocytomas possessed lower CK activity than anaplastic astrocytomas and glioblastomas and, in addition, tended to possess lower CK content than normal brain. No qualitative changes of the normal CK isoenzyme pattern were observed in the tumours.

Adult↗

PubMed2002

Role of C-terminal sequences in the folding of muscle creatine kinase.

Proteinase K selectively nicks the native homodimeric muscle creatine kinase (MM-CK) into two 37.1 kDa N-terminal (K1) and two 5.8 kDa C-terminal (K2) fragments that remain firmly associated in a native-like, although inactive, heterotetrameric structure. This truncated protein has been named (K1K2)(2). To analyze the role of the C-terminal peptide in the protein structure acquisition, we studied in vitro refolding of the guanidinium chloride-denatured (K1K2)(2). Although they never reassociate with K2, in selected conditions the K1 fragments refold slowly to a dimeric state as shown by size exclusion chromatography data. This K1 dimer exhibits a fluorescence emission lambda max of 335 nm, a high degree of tyrosine exposure, strongly binds ANS but not MgADP, a CK substrate, and according to these structural characteristics, could be a dimeric molten globule species. We propose a folding model that takes into account the existence of a new transient intermediate state in the MM-CK refolding process. Besides two monomeric premolten and molten globule kinetic intermediates and the active final dimeric form, an inactive dimer, with partly compacted monomers, must ephemerally exist. Our results strongly suggest that the C-terminal end of the protein accelerates folding and plays a critical role for monomer final packing into a native-like conformation. The data also indicate that MM-CK catalytic efficiency is only acquired after dimerization.

Chromatography, Gel↗

PubMed2001

Gene duplication events producing muscle (M) and brain (B) isoforms of cytoplasmic creatine kinase: cDNA and deduced amino acid sequences from two lower chordates.

Creatine kinase (CK) is coded for by at least four loci in higher vertebrates--two cytoplasmic isoforms, muscle (M) and brain (B), and two mitochondrial isoforms, sarcomeric and ubiquitous. M is expressed primarily in skeletal muscle, while B is expressed in a variety of cells, including cardiac and smooth muscle fibers, neurons, transport epithelia, and photoreceptors. M and B subunits form very stable homodimers (MM [M-CK], BB [B-CK]) and heterodimers (MB). M-CK is capable of binding to the M line of the myofibril, thereby creating an energy transfer microcompartment; BB and MB CKs are not. M- and B-like CKs are present in all vertebrates yet examined, including fish. Cytoplasmic, dimeric CKs are widely distributed in the invertebrates. The only available amino acid sequence for an invertebrate dimeric CK, that of the protostome polychaete Chaetopterus variopedatus, is just as similar to the vertebrate M isoform as to the B isoform. Echinoderms lack dimeric, cytoplasmic CKs, which appear to be replaced by a dimeric arginine kinase which evolved secondarily from CK. Thus, it is likely that the gene duplication event producing the M and B isoforms occurred after the divergence of the chordates from echinoderms. To narrow down the timing of this duplication event, we obtained the cDNA and deduced amino acid sequences of dimeric CKs from the tunicate Ciona intestinalis (subphylum Urochordata) and the lancelet Branchiostoma floridae (subphylum Cephalochordata). Our results show that these CKs are strikingly similar to both invertebrate and vertebrate CKs. However, phylogenetic analyses by neighbor-joining and parsimony show that these two enzymes appeared to have diverged before the point of divergence of the M and B isoforms. Thus, the gene duplication event for formation of the muscle and brain isoforms of CK most likely occurred during the radiation of the fish, a time noted for gene duplication events at a variety of other loci.

Amino Acid Sequence↗

PubMed1991

Alveolar soft part sarcoma of the pulmonary vein.

Alveolar soft part sarcoma of the lung seen in a 42-year-old female is reported. In the partial pneumonectomy specimen, there was a 3 x 2.5 cm tumor arising from the pulmonary vein at the level of the right lung hilus, with tumor thrombus formation. The transition between the tumor and venous smooth muscle layer was microscopically confirmed. At autopsy, performed 18 months after surgery, metastases were noted in the left lung and brain. No primary focus was identified in the soft tissue. The alveolus-forming clear tumor cells contained diastase-resistant periodic acid-Schiff-reactive granules. Immunohistochemically, granular cytoplasmic reactivities with monoclonal antibodies against pan-actin and alpha-sarcomeric actin were demonstrated, whereas other muscle markers such as desmin, alpha-smooth muscle actin, myoglobin, fast skeletal myosin, and the mm-isozyme of creatine kinase were negative. Ultrastructurally, crystallized structures were occasionally identified in the membrane-bound, electron lucent granules, which often filled the tumor cell cytoplasm. The muscle cell nature of the neoplasm is discussed.

Adult↗

PubMed1983

A new creatine kinase found in mitochondrial extracts from malignant liver tissue.

A new creatine kinase (CK, ATP: creatine N-phosphotransferase, EC 2.7.3.2) band was found in mitochondrial extracts prepared from malignant liver tissue. By agar gel electrophoresis the new band (CKmLT) migrated between CK-MM and a sample application point. The CK band was not found in mitochondrial extracts of normal liver, cytosolic extracts of normal and malignant liver homogenates. We thus presume that the origin of CKmLT is from mitochondria of malignant liver tumors. CKmLT reacted with anti-mitochondrial CK antibodies so that its antigenicity was similar to that of mitochondrial CK. Physico-chemical characteristics were similar to those of the polymeric form of the normal liver mitochondrial CK (CKmL1); i.e. relative molecular mass (320 000 to 350 000), heat stability, and the behavior in 2 mol/l urea. CKmLT migrated to the CKmL1 and the MM position after long-term storage at -20 degrees C. CKmLT did not demonstrate affinity to concanavalin A, and there was no significant change in the electrophoretic mobility of CKmLT following neuraminidase treatment.

Adult↗

PubMed1985

Comparison of enzymatic characteristics of creatine kinase BB from human healthy and tumor stomach tissues.

Creatine kinase (ATP: creatine N-phosphotransferase, EC 2.7.3.2, CK) BB isoenzyme from stomach tumor tissue was partially purified and its characteristics were compared with those from healthy tissue. Molecular mass of tumor CK-BB was estimated to be 82 000 by polyacrylamide gel electrophoresis. Tumor CK-BB was separated into 2 main subbands around pH 4.5 and 11, minor subbands around pH 5-7.5 by agarose isoelectric focusing. The isoenzyme reacted with anti-human brain CK-BB antibodies and formed a hybrid, CK-MB, with CK-MM prepared from healthy human skeletal muscle. The above physicochemical and immunological characteristics of tumor CK-BB were the same as those of normal CK-BB from normal stomach tissue. Optimum pH of tumor CK-BB was more acidic than that of normal CK-BB. Affinity for creatine phosphate and heat sensitivity of tumor CK-BB were slightly lower than those of normal CK-BB. Tumor CK-BB was more stable after iodoacetamide and urea treatments.

Brain↗

PubMed1990

Alveolar soft part sarcoma. A clinicopathologic and immunohistochemical study of 12 cases.

Twelve cases of alveolar soft part sarcoma (ASPS) were reviewed. Seven of them arose primarily in the lower extremities, three in the head and neck region, and two in other parts. ASPSs in the head and neck region occurred in children before 10 years of age, whereas ASPSs in the other regions occurred in rather older patients. Moreover, ASPSs of the head and neck were relatively small in size, and were diagnosed earlier than those in other regions. Histologically, six cases (including all the head and neck cases) contained considerable area of small and indistinct alveolar structures. Four cases showed remarkable cellular pleomorphism. Immunohistochemical demonstration of vimentin, desmin, the beta-subunit of enolase and the MM isozyme of creatine kinase, together with the absence of immunoreactive cytokeratin, supported the myogenic nature of this rare tumor. A small number of S-100 protein-positive tumor cells were also observed. Follow-up data for these cases disclosed that the tumors containing considerable area of small alveoli and uniform small tumor cells formed distant metastases at an early stage.

Adolescent↗

PubMed1985

Early detection of myocardial infarction in conscious dogs by analysis of plasma MM creatine kinase isoforms.

To determine whether myocardial infarction could be detected early after onset by analysis of subforms of the MM isoenzyme (isoforms) of creatine kinase (MM CK) in plasma, we subjected eight conscious dogs to coronary occlusion and quantified isoforms in serial plasma samples by chromatofocusing. The fractions of MMA (isoelectric point [pI] = 7.91), MMB (pI = 7.74), and MMC (pI = 7.51) in plasma samples before coronary occlusion averaged 11.4 +/- 4.8% (SD), 22.3 +/- 5.5%, and 66.3 +/- 9.6% of total MM CK activity. The fraction of MMA, the isoform of MM CK found in myocardium, increased significantly in plasma 1 hr after coronary occlusion, reached a maximum of 49.7 +/- 8.0% in 4.1 +/- 1.3 hr, and returned to baseline in 12.0 +/- 2.3 hr. The fraction of plasma MM CK activity attributable to MMC, an isoform formed slowly in plasma from MMA via MMB as an intermediate, decreased significantly within 1 hr, reached a minimum of 14.0 +/- 4.1% in 4.8 +/- 1.1 hr, and returned to baseline in 13.0 +/- 2.9 hr after coronary occlusion. Total CK activity did not increase significantly until later, i.e., 5 hr after occlusion, and peaked at 1371 +/- 530 IU/liter in 10.9 +/- 1.9 hr. Within the first 4 hr after coronary occlusion, MMA consistently comprised more than 20% of plasma MM CK activity despite insignificant increase of total CK. Changes in isoform proportions were consistent and independent of peak total CK activity and of cumulative CK release over a 10-fold range. Thus initial CK release indicative of infarction is detectable within 1 hr after the onset of ischemia by quantification of plasma MM CK isoforms.

Animals↗

PubMed1993

The mature form of imported mitochondrial proteins undergoes conformational changes upon binding to isolated mitochondria.

Mature mitochondrial proteins (aspartate aminotransferase, malate dehydrogenase, hydroxyacyl coenzyme A dehydrogenase, creatine kinase) and cytosolic proteins (aldolase, glyceraldehyde-3-phosphate dehydrogenase) with a basic pI were found to bind to isolated mitochondria, electrostatic interactions being mainly responsible for their binding. Mitochondrial aspartate aminotransferase bound with a Kd' of 30 nM in 0.6 M sorbitol, 20 mM Hepes/KOH, pH 7.4, at 25 degrees C. Cytosolic aspartate aminotransferase and glutamate dehydrogenase (a protein located in the mitochondrial matrix) both with an acidic pI, did not bind to mitochondria. Treatment of mitochondria with proteinases did not affect the subsequent binding of imported mitochondrial proteins. Their association with both intact and proteinase-treated mitochondria resulted in a marked increase in their susceptibility toward proteinase K. In contrast, the basic cytosolic proteins tested bound only to intact mitochondria and thereby did not become more susceptible toward proteolytic attack. Treatment of mitochondria with adriamycin, a drug binding to acidic phospholipids, prevented the subsequent association of mitochondrial aspartate aminotransferase with mitochondria and the ensuing conformational labilization. Apparently, the mature moiety of imported mitochondrial proteins is partially unfolded upon interaction with the lipid component of the mitochondrial envelope. Both the binding of the mitochondrial proteins and their conformational labilization is independent of ATP and the electrochemical potential across the inner membrane.

3-Hydroxyacyl CoA Dehydrogenases↗