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PubMed1988

Two monoclonal antibody lines directed against subunit IV of cytochrome oxidase: a study of opposite effects.

Two monoclonal lines of antibodies were isolated with specificities against the amino half of Subunit IV of beef heart cytochrome oxidase. The lines had nonoverlapping epitopes. Both bound to the matrix face of membranous oxidase, neither bound to the cytoplasmic face. One line (QA4/C4) stimulated electron transfer in soluble or membranous oxidase, while the other (QA4) inhibited that activity by both oxidase preparations. These effects on electron transfer activity were not altered by the inclusion or omission of detergent. ATP depressed the binding of either antibody to either soluble or membranous oxidase. In the absence of ATP, QA4/C4 stimulated electron transfer only in the high affinity phase of cytochrome c oxidation (with decreased KM and increased Vmax), causing slight inhibition in the low affinity phase (with decreased KM). In the presence of ATP, QA4/C4 abolished the high affinity phase, but did not alter the ATP influence on the low affinity phase. In the absence of ATP, antibodies of line QA4 abolished the low affinity phase, leaving a high affinity phase similar to that induced by ATP. In the presence of ATP, QA4 abolished the high affinity phase, leaving a low affinity phase similar to that seen with ATP alone. This behavior is consistent with the dissection of two catalytic sites for cytochrome c and more than one ATP affector site.

Adenosine Triphosphate↗
PubMed1991

Effects of cortical and thalamic lesions upon primary afferent terminations, distributions of projection neurons, and the cytochrome oxidase pattern in the trigeminal brainstem complex.

Early postnatal lesions of the primary somatosensory cortex alter the vibrissa-related cytochrome oxidase (CO) pattern in nucleus principalis (PrV) of the rat's trigeminal (V) brainstem complex (Erzurumlu and Ebner, '88: Dev. Brain Res. 44:302-308). At present, the reason for this change is not clear. It may be that the corticotrigeminal projection is necessary for the maintenance of vibrissa-related patterns in PrV. However, it is also possible that the loss of the normal pattern of CO activity reflects a change in the organization of brainstem cells resulting from transneuronal retrograde degeneration. In order to address this question, we made lesions of either the primary somatosensory cortex (S-I) or ventrobasal thalamus (VB) in newborn rats and directly assayed distribution of V primary afferents by transganglionic transport of horseradish peroxidase and V-thalamic neurons by retrograde transport of either fluorogold or true blue. Neonatal cortical and thalamic lesions produced no qualitative change in the distribution of primary afferent terminals in either PrV or V subnucleus interpolaris (SpI) beyond that which could be attributed to shrinkage of the brainstem resulting from retrograde degeneration. Most importantly, the "patchy" pattern of terminations observed in normal rats remained apparent in the brain-damaged animals. The normal distribution of V-thalamic neurons in PrV was disrupted by both cortical and thalamic lesions. These cells are normally patterned in a way that matches the distribution of primary afferent terminals and thus that of the mystacial vibrissae. This was not the case in the neonatally brain-damaged rats. Taken together, these results are consistent with the conclusion that neonatal cortical and thalamic lesions disrupt the normal CO pattern in PrV primarily because of their effects upon the patterning of brainstem cells. The present findings demonstrate further that clustering of primary afferents does not require a normal complement of postsynaptic neurons.

Afferent Pathways↗
PubMed1987

Structural models of the redox centres in cytochrome oxidase.

Evolutionary conservation, predicted membrane topography of the subunits, and known chemical and physical properties of the catalytic metals in cytochrome oxidase provided the basis for plausible structural models of the enzyme's redox centres. Subunit II probably binds one of the copper ions (CuA) whilst subunit I is likely to bind the two haems (a and a3) and the other redox-active copper (CuB). Two cysteine and two histidine residues of subunit II are the likely ligands of CuA, forming a centre that may be structurally similar to that in azurin. The two haems may be sandwiched between two transmembranous segments of subunit I, one of which also provides a histidine ligand to CuB. A third segment may provide two more histidine ligands to the latter. The model was constructed with a 4 A Fe-Cu distance in the binuclear haem a3-CuB centre, and a 14 A distance between the haem irons. The subunit I model involves only three transmembranous helices which bind three catalytic metal groups. The fit of this model to several known physicochemical properties of the redox centres is analysed.

Animals↗
PubMed1986

Expression of the mitochondrial split gene coding for cytochrome oxidase subunit I in S. cerevisiae: RNA splicing pathway.

We have studied the splicing pathway leading to the synthesis of cytochrome oxidase subunit I (COX I) mRNA, by analysing the transcription pattern of several oxi3- splicing deficient mutants located in the first four introns of the gene. The four introns contain long open reading frames (ORFs) in phase with the upstream exons. All the mutations block the excision of the mutated intervening sequence (IVS) from the pre-mRNA, and accumulate characteristic novel polypeptides of sizes which could correspond to the translation products of the intron's ORF. Most of the mutations do not affect the splicing of the following intervening sequences; only in the case of mutations in the aI1 intron is a polar effect observed on the splicing of the second intron, aI2. Our results indicate that the splicing of these two intervening sequences which both belong to the class II of introns described by Michel et al. (1982), is controlled by the activity of the maturases encoded by their respective ORFs and that the translation of the aI2 maturase depends on the previous excision of aI1 IVS. (Moreover, the aI1 maturase, which accumulates in some mutants, can efficiently splice aI2 IVS when the translation of the latter's proper maturase cannot occur).

Electron Transport Complex IV↗
PubMed1993

An optimized method for determining cytochrome oxidase activity in brain tissue homogenates.

We have developed a method to accurately and reproducibly determine the total activity of cytochrome oxidase (CO) in rat brain tissue homogenates. Previously, accurate measurements have been difficult to obtain because detergents, which are needed to disrupt membranes and unmask CO, also inhibit the enzyme by solubilizing certain phospholipids required for rapid turnover. We compared various methods of sample preparation, and found that maximal CO activity in homogenates could be obtained using specific concentrations of detergents. The range of optimal detergent concentrations was relatively narrow, as CO activity fell sharply with small deviations from the optimum. Of 5 detergents tested, deoxycholate stimulated CO maximally over the widest range of concentrations. In deoxycholate-treated homogenate samples, the calculated CO turnover number was about 480 s-1, indicating that overall enzyme activity was maximal or near maximal, and therefore that the total content of CO was probably detected. This method was reproducible with large or small samples (e.g., < 1 mg tissue), and should be applicable to studies of neural tissue in general.

Animals↗
PubMed2005

Labeling of cytochrome oxidase patches in intact flatmounts of striate cortex.

Primate striate cortex contains a prominent system of columns referred to as cytochrome oxidase (CO) patches. Studies directed at the morphology and interconnections of cells in patches would be facilitated by a method that revealed the location of patches in the intact cortex. In three adult rhesus monkeys we prepared flatmounts of striate cortex [Horton JC, Hocking DR. Intrinsic variability of ocular dominance column periodicity in normal macaque monkeys. J Neurosci 1996;16:7228-39; Sincich LC, Adams DL, Horton JC. Complete flatmounting of the macaque cerebral cortex. Vis Neurosci 2003;20:663-86]. The flattened specimens were then reacted for CO activity prior to sectioning. Transillumination of the intact cortical sheet revealed an extensive pattern of dark ovals. It was confirmed that this pattern corresponded to the CO patches by subsequently cutting tangential sections and comparing them with images from the intact block. In vitro labeling of CO patches in the intact striate cortex may prove useful for directing injections of anatomical tracers such as Lucifer Yellow or DiI into identified patch and interpatch compartments.

Animals↗
PubMed1993

Resolution of the reaction sequence during the reduction of O2 by cytochrome oxidase.

Time-resolved resonance Raman spectroscopy has been used to study the reduction of dioxygen by the mitochondrial enzyme, cytochrome oxidase. In agreement with earlier reports, Fe(2+)-O2 and Fe(3+)-OH- are detected in the initial and final stages of the reaction, respectively. Two additional intermediates, a peroxy [Fe(3+)-O(-)-O-(H)] and a ferryl (Fe4+ = O), occur transiently. The peroxy species shows an oxygen-isotope-sensitive mode at 358 cm-1 that is assigned as the nu(Fe(3+)-O-) stretching vibration. Our kinetic analysis indicates that the peroxy species we detect occurs upon proton uptake from bulk solution; whether this species bridges to Cu(B) remains uncertain. For the ferryl, nu(Fe(4+) = O) is at 790 cm-1. In our time-resolved spectra, the 358 cm-1 mode appears prior to the 790 cm-1 vibration. By using kinetic parameters deduced from the time-resolved Raman work and from a variety of time-resolved optical studies from other laboratories, we have assigned rate constants to several steps in the linear reaction sequence proposed by G. T. Babcock and M. Wikström [(1992) Nature (London) 356, 301-309]. Simulations of this kinetic scheme provide insight into the temporal behavior of key intermediates in the O2 reduction process. A striking aspect of the reaction time course is that rapid O2-binding and trapping chemistry is followed by a progressive slowing down of succeeding steps in the process, which allows the various transient species to build up to concentrations sufficient for their detection by our time-resolved techniques. Our analysis indicates that this behavior reflects a mechanism in which conditions that allow efficient dioxygen bond cleavage are not inherent to the active site but are only established as the reaction proceeds. This catalytic strategy provides an effective means by which to couple the free energy available in late intermediates in the reduction reaction to the proton-pumping function of the enzyme.

Animals↗
PubMed2000

Oxygen dependency and precision of cytochrome oxidase signal from full spectral NIRS of the piglet brain.

Oxidation changes of the copper A (Cu(A)) center of cytochrome oxidase in the brain were measured during brief anoxic swings at both normocapnia and hypercapnia (arterial PCO(2) approximately 55 mmHg). Hypercapnia increased total hemoglobin from 37.5 +/- 9.1 to 50.8 +/- 12.9 micromol/l (means +/- SD; n = 7), increased mean cerebral saturation (Smc(O(2))) from 65 +/- 4 to 77 +/- 3%, and oxidized Cu(A) by 0.43 +/- 0.23 micromol/l. During the onset of anoxia, there were no significant changes in the Cu(A) oxidation state until Smc(O(2)) had fallen to 43 +/- 5 and 21 +/- 6% at normocapnia and hypercapnia, respectively, and the maximum reduction during anoxia was not significantly different at hypercapnia (1.49 +/- 0.40 micromol/l) compared with normocapnia (1.53 +/- 0.44 micromol/l). Residuals of the least squares fitting algorithm used to convert near-infrared spectra to concentrations are presented and shown to be small compared with the component of attenuation attributed to the Cu(A) signal. From these observations, we conclude that there is minimal interference between the hemoglobin and Cu(A) signals in this model, the Cu(A) oxidation state is independent of cerebral oxygenation at normoxia, and the oxidation after hypercapnia is not the result of increased cerebral oxygenation.

Animals↗
PubMed1988

[Evaluation of the adequacy of hypotensive therapy based on the status of the tissue oxygen system and serum lactate dehydrogenase and cytochrome oxidase activities in patients with hypertension].

Parameters of tissue oxygen regime measured by polarography and serum lactate dehydrogenase (LDG) and cytochrome oxidase (CO), oxidation-reduction enzymes, were studied in 23 patients with stable hypertension of various hemodynamic types. The nature of the tissue oxygen regime and changes observed in the isoenzymic spectra of LDG and CO were found to be associated with BP levels, hemodynamic types and BP reduction degree. The time course of these values may be useful in assessing whether the antihypertensive therapy is appropriate and in determining an optimal level of BP decrease.

Adult↗
PubMed1990

Monomer-dimer structure of cytochrome-c oxidase and cytochrome bc1 complex from the thermophilic bacterium PS3.

Molecular weights of three membrane proteins have been measured in the presence of 0.1% octaethylene glycol n-dodecyl ether (C12E8) by the measuring system in which a membrane protein eluted from a gel chromatography column is monitored sequentially for ultraviolet absorption, light scattering and refractive index. The relative molecular mass (Mr) and amount of bound detergent per protein (delta) can be calculated from these data, if instrumental constants are measured using a set of appropriate water-soluble proteins which does not bind nonionic surfactants. The molecular masses of cytochrome c oxidase and cytochrome bc1 complex from the thermophilic bacterium PS3 were determined to be 127 kDa and 185 kDa, respectively, indicating that the oxidase is monomeric, while the bc1 complex dimeric in the presence of C12E8. The larger apparent molecular mass of about 310 kDa of the PS3 oxidase obtained from the retention time of the gel chromatography (Sone, N., Sekimachi, M. and Kutoh, E. (1987) J. Biol. Chem. 262, 15386-15391) turned out to be due to a high binding ability with the detergent (delta = 1.25 g/g) of this very hydrophobic protein. Analyses of bovine heart cytochrome oxidase, on which monomer/dimer properties have been reported, showed that the enzyme is mainly dimeric (Mr = 374,000), while a small portion is monomeric (Mr = 191,000). Mild alkaline treatment of this enzyme caused monomerization of the enzyme with accompanying aggregate formation. These results, thus, show that this method is suitable to analyze monomer/dimer conversion of membrane protein as well as to estimate structure of membrane proteins.

Animals↗
PubMedDate not supplied

Flow-flash, time-resolved resonance Raman spectroscopy of the oxidation of reduced and of mixed valence cytochrome oxidase by dioxygen.

Time-resolved resonance Raman spectroscopy has been used to study the reduction of oxygen by both reduced and mixed valence cytochrome oxidase. Laser flash photodissociation of CO from the carbon monoxy complex of the enzyme, after this species had been rapidly mixed with oxygenated buffer, was used to initiate the reaction for both forms of the enzyme. The CO photolysis product of the mixed valence enzyme contains cytochrome a3+ and cytochrome a3(2+) in its unligated form. This species reacts with O2 in the first few microseconds to form a photolabile intermediate which has Raman frequencies characteristic of oxygenated heme. This indicates that an oxyhemoglobinlike complex of oxygen with a3(2+) is the precursor to oxygen reduction. A similar intermediate is detected in the fully reduced enzyme reaction. In the mixed valence oxidase system, the oxy intermediate is replaced by a nonphotolabile species in which a3 is oxidized with t1/2 approximately equal to 200 musec. These results demonstrate the feasibility of applying time-resolved vibrational techniques to irreversible electron transfer reactions and, in particular, elucidate some of the transient species in the cytochrome oxidase/O2 system.

Carbon Monoxide↗
PubMed1988

Laminar and sublaminar ultracytochemical localization of cytochrome oxidase in the optic tectum of normal goldfish.

Distinct laminae and sublaminae in the goldfish optic tectum exhibit substantial differences in cytochrome oxidase (C.O.) reactivity. To determine whether these differences are associated with differential reactivity of different neuronal profiles, each tectal sublamina was examined at the ultrastructural level following C.O. treatment. The greatest abundance of darkly reactive mitochondria was found in the optically innervated layers within both pre- and postsynaptic profiles in correspondence with the most intense staining of these layers at the light microscopic level. Many reactive mitochondria were localized within terminals that were presumed to be optic on the basis of cytological criteria or were shown to be optic by filling optic fibers with HRP and processing so as to simultaneously demonstrate both mitochondrial C.O. reactivity and HRP labeling. These optic terminals tended to differ from each other in size and level of reactivity. The largest terminals were located within sublamina d of the stratum fibrosum et griseum superficials (SFGSd), and these were the most intensely reactive and contained the greatest number of darkly reactive mitochondria. Medium-sized terminals were found within sublaminae SFGSa, SFGSb, and a and c of the stratum album centrale (SACa,c). These were also darkly reactive but contained fewer mitochondria. Other medium-to-small optic terminals were found in stratum opticum a and b (60a,b), SFGSb, SFGSc, and stratum griseum centrale c (SGCc). These typically contained fewer mitochondria that also tended to be relatively less reactive, although darkly reactive mitochondria were also present. We suggest that the metalbolic differences within optic terminals of different size and sublaminar stratification arise from different ganglion cell classes and that the different optic layers of tectum are functionally substratified. As expected, darkly reactive mitochondria were most abundant in th intensely stained sublaminae, which included the optic lamina SFGS and nonoptic sublamina SGCa, and they were found not only within optic terminals but also within dendrites, presynaptic dendrites, and nonoptic terminals as well. Glial processes tended to contain less reactive mitochondria. The most prominent of the nonoptic terminals were the large-diameter P1 terminals, which contained pleomorphic vesicles and formed symmetric (presumed inhibitory) synapses. In stratum marginale most of the darkly reactive mitochondria were localized within dendrites. In the rest of the tectal layers most of the darkly reactive mitochondria were found in both presynaptic terminals and dendrites.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Cytochrome oxidase subunit II gene is adjacent to an initiator methionine tRNA gene in soybean mitochondrial DNA.

The nucleotide sequence of the cytochrome oxidase subunit II (COII) gene from soybean mitochondria reveals a high degree of sequence conservation to other plant COII sequences. The greatest homology is to pea (97.9%) and the homology extends for some distance both 5' and 3' from the gene. Upstream from the breakpoint in homology with the pea sequence there is a tRNA gene identified as the initiator methionine by homology to known plant tRNA genes. The COII coding sequence appears to be present at a single location in the soybean mitochondrial genome, however some portion of the 5' flanking region is repeated at other sites in the genome. The transcription from the cloned region is complex and is complicated by the presence of the repeated sequence.

Amino Acid Sequence↗
PubMed1990

Cytochrome oxidase from thermophilic bacterium PS3 contains a fourth protein subunit.

Monoclonal antibodies prepared against subunits II and IV of beef heart cytochrome oxidase were found to cross-react with thermophilic bacterial PS3 oxidase. Each individual antibody affects the enzymatic activity. "Western" blot analyses showed that subunit II antibodies of beef heart recognized subunit II of PS3 and subunit IV antibody likewise recognized a fourth protein subunit on slab gels. This fourth subunit previously thought to be a contaminant or a degradation product has a molecular weight of about 10,500 on SDS-gels, and appears to exist in stoichiometric amount. We have extracted this subunit from slab gels and compared its amino acid composition with that of subunit III.

Amino Acids↗
PubMed1992

Localization of cytochrome oxidase (COX) activity and COX mRNA in the hippocampus and entorhinal cortex of the monkey brain: correlation with specific neuronal pathways.

Cytochrome oxidase (COX) activity and COX II mRNA expression were localized in the hippocampal formation and entorhinal cortex of the rhesus monkey brain by means of enzyme histochemistry and in situ hybridization, respectively. Within the hippocampal formation, the terminal field of the perforant pathway showed the highest levels of COX activity, whereas COX II mRNA was localized mainly in neuronal cell bodies. In the entorhinal cortex. COX II mRNA was detected in neuronal cell bodies of layers II and IV. These results indicate that the pattern of localization of COX and its mRNA in entorhinal cortex correlates with the input and output pathways of the hippocampus.

Animals↗
PubMed2000

O-O bond splitting mechanism in cytochrome oxidase.

Hybrid density functional theory (DFT) calculations have been used to investigate different mechanisms for O-O bond splitting in cytochrome oxidase. It is shown that the requirement for a low activation barrier for the O-O bond splitting is that two protons, apart from the tyrosine hydroxyl proton, are available at the binuclear center. A mechanism is suggested for the transformation from a species with a molecularly coordinated O2, to an O-O cleaved species with an oxo-ferryl group. The mechanism has a calculated activation barrier in reasonable agreement with experimental estimates, and the overall reaction is close to thermoneutral, in line with the requirement that the energy wasted as heat should be minimized. The rate limiting step in the mechanism occurs at the initial Fe-O2 intermediate, consistent with experimental observations that the decay of the oxy intermediate parallels the increase of the oxo product. The formation of a radical at the cross-linked tyrosine-histidine structure is a possible source for one of the electrons required in the bond cleavage process. Possible sources for the two protons are discussed, including a suggested key role for the hydroxyl group on the farnesyl side chain of heme a3.

Animals↗
PubMed1997

Reduced cytochrome oxidase and memory dysfunction after chronic brain ischemia in aged rats.

The effects of chronic cerebrovascular ischemia on memory function and cytochrome oxidase (CO) activity were investigated. Cerebrovascular insufficiency was induced by permanent bilateral carotid artery ligation (2-VO) in 19 month old rats. Sham surgery in no-vessel occlusion (no-VO) rats were used for controls. Memory function was tested 1 week prior to surgery and then weekly for 21 days using the Morris water maze. Regional brain activity of CO was measured 4 weeks after surgery by quantitative histochemistry. Histologic examination of brain slices was used to evaluate any neuropathology present. Results showed that 2-VO rats were significantly impaired in the water maze task at each testing period with respect to no-VO controls. In addition, CO activity in 2-VO rats was markedly reduced only in the dorsal CA1 region of the hippocampus and in the posterior parietal cortex. These brain regions are involved in visuo-spatial memory mechanisms. Analysis of other brain regions in 2-VO rats did not reveal further CO activity changes. There were no damaged or loss of neurons in 2-VO or no-VO groups in any region examined, including CA1 and posterior parietal cortex. The CA1 region however, is known to undergo neuronal loss 25 weeks after chronic 2-VO suggesting that this vascular insult can induce a slowly-evolving cascade consisting of neuronal damage, atrophy and death. The present findings indicate that reduced CO activity in CA1 and posterior parietal regions can predict neural damage and atrophy prior to structural perikaryal pathology following chronic brain ischemia. In addition, the data shows that neuronal energy metabolic deficiency may initiate visuo-spatial memory impairment in this aging rat model.

Aging↗