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PubMed2001

Release of amines from acidified stores following accumulation by Transport-P.

1. Transport-P is an uptake process for amines in peptidergic neurones of the hypothalamus. It differs from other uptake processes by its anatomical location in post-synaptic neurones, its functional properties and by the structure of its ligands. Transport-P accumulates amines in intracellular vesicles, derives its energy from the electrochemical proton gradient and is linked to vacuolar-type ATPase (V-ATPase). Transport-P is blocked by antidepressants. We have now studied the release of amines following uptake by Transport-P in a cell line of hypothalamic peptidergic neurones. 2. Release of prazosin was not inhibited by the antidepressant desipramine; as Transport-P is blocked by desipramine, this indicated that amines are released by a mechanism which is independent of Transport-P. 3. Release of prazosin was sensitive to temperature and conformed to the Arrhenius equation. Release was minimal in the range 0-25 degrees C but accelerated exponentially at higher temperatures up to 33 degrees C. The activation energy for the release of prazosin is 83.1 kJ x mol(-1), corresponding to a temperature quotient (Q10) value of 3. 4. Release was accelerated by the organic base chloroquine, the ionophore monensin, bafilomycinA1 which inhibits V-ATPase and by increasing extracellular pH. Thus, retention of prazosin requires an intracellular proton gradient which is generated by V-ATPase. 5. Fluorescence microscopy demonstrated that release of BODIPY FL prazosin was temperature dependent and was accelerated by chloroquine and monensin. 6. Thus, following uptake by Transport-P, amines are accumulated in acidified intracellular stores. Their retention in peptidergic neurones requires intracellular acidity. The amines are released by a temperature-dependent process which is resistant to antidepressants.

Antidepressive Agents↗
PubMed2001

Analysis of the muscarinic receptor subtype mediating inhibition of the neurogenic contractions in rabbit isolated vas deferens by a series of polymethylene tetra-amines.

The pharmacological characteristics of the presynaptic muscarinic receptor subtype, which mediates inhibition of the neurogenic contractions in the prostatic portion of rabbit vas deferens, have been investigated by using a series of polymethylene tetra-amines, which were selected for their ability to differentiate among muscarinic receptor subtypes. It was found that all tetra-amines antagonized McN-A-343-induced inhibition in electrically stimulated rabbit vas deferens in a competitive manner and with affinity values (pA:(2)) ranging between 6.27+/-0.09 (spirotramine) and 8.51+/-0.02 (AM170). Competition radioligand binding studies, using native muscarinic receptors from rat tissues (M(1), cortex; M(2), heart; M(3), submaxillary gland) or from NG 108-15 cells (M(4)) and human cloned muscarinic M(1)-M(4) receptors expressed in CHO-K1 cells, were undertaken with the same tetra-amines employed in functional assays. All antagonists indicated a one-site fit. The affinity estimates (pK:(i)) of tetra-amines calculated in binding assays using native receptors were similar to those obtained using cloned receptors. Among these compounds some displayed selectivity between muscarinic receptor subtypes, indicating that they may be valuable tools in receptor characterization. Spirotramine was selective for M(1) receptors versus all other subtypes (pK:(i) native: M(1), 7.32+/-0.10; M(2), 6.50+/-0.11; M(3), 6.02+/-0.13; M(4), 6.28+/-0.16; pK:(i) cloned: M(1), 7.69+/-0.08; M(2), 6.22+/-0.14; M(3), 6.11+/-0.16; 6.35+/-0.11) whereas CC8 is highly selective for M(2) receptors versus the other subtypes (pK:(i) native: M(1), 7.50+/-0.04; M(2), 9.01+/-0.12; M(3), 6.70+/-0.08; M(4), 7.56+/-0.04; pK:(i) cloned: M(1), 7.90+/-0.20; M(2), 9.04+/-0.08; M(3), 6.40+/-0.07; M(4), 7.40+/-0.04). Furthermore, particularly relevant for this investigation were tetra-amines dipitramine and AM172 for their ability to significantly differentiate M(1) and M(4) receptors. The apparent affinity values (pA:(2)) obtained for tetra-amines in functional studies using the prostatic portion of rabbit vas deferens correlated most closely with the values (pK:(i)) obtained at either native or human recombinant muscarinic M(4) receptors. This supports the view that the muscarinic receptor mediating inhibition of neurogenic contractions of rabbit vas deferens may not belong to the M(1) type but rather appears to be of the M(4) subtype.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed2004

Multinuclear platinum(II)-amine complexes containing bis(aminopropyl)dicarba-closo-dodecaborane(12) ligands.

Treatment of the bridging bidentate 1,Z-bis(aminopropyl)-1,Z-dicarba-closo-dodecaborane(12)(1,Z-bis(aminopropyl)-1,Z-carborane) ligands of the type 1,Z-[H(2)N(CH(2))(3)](2)-1,Z-C(2)B(10)H(10)(L(1), Z= 7, 5) or (L(2), Z= 12, 6) with two equivalents of trans-[PtClI(2)(NH(3))](-), followed by halogen ligand metathesis with AgOTf and HCl((aq)) afforded the novel diplatinum(II)-amine species cis-[[PtCl(2)(NH(3))](2)L(n)](7(n= 1) or 8(n= 2), respectively). Similarly, the reaction of L(1) or L(2) with the labile trans-[PtCl(dmf)(NH(3))(2)](+) afforded trans-[[PtCl(NH(3))(2)](2)L(n)](OTf)(2)(9(n= 1) or 10(n= 2), respectively) in good yield and purity. However, isolation of the analogous 1,2-carborane complexes was not possible owing to decomposition reactions that led to extensive degradation of the carborane cage and reduction of the metal centre. The mixed dinuclear complex [cis-[PtCl(2)(NH(3))]-L(1)-trans-[PtCl(NH(3))(2)]]OTf (19) was prepared by treatment of the Boc-protected amine ligand 1-[(Boc)(2)N(CH(2))(3)]-7-[H(2)N(CH(2))(3)]-1,7-C(2)B(10)H(10)(L(3), 15) with trans-[PtCl(dmf)(NH(3))(2)](+) to yield trans-[PtCl(NH(3))(2)L(3)]OTf (16), followed by acid deprotection of the pendant amine group, complexation with trans-[PtClI(2)(NH(3))](-), and halogen ligand metathesis using AgOTf and HCl((aq)). A novel trinuclear species containing 5 was prepared by the addition of two equivalents of 15 to the labile precursor cis-[Pt(dmf)(2)(NH(3))(2)](2+) followed by acid deprotection of the pendant amine groups. Further complexation with two equivalents of trans-[PtClI(2)(NH(3))](-) followed by halogen ligand metathesis using AgOTf and HCl((aq)) afforded the triplatinum(II)-amine species [cis-[Pt(NH(3))(2)(L(1))(2)]-cis-[PtCl(2)(NH(3))](2)](OTf)(2)(23). Complexes 7-10, 19 and 23 represent the first examples of multinuclear platinum(ii)-amine derivatives containing carborane cages. Preliminary in vitro cytotoxicity studies for selected complexes are also reported.

Journal Article↗
PubMed1993

Biogenic-amine acetylation: an additional function of the N-acetyltransferase from Fasciola hepatica.

The previously described polyamine N-acetyltransferase from Fasciola hepatica has been observed to have an additional function, the acetylation of biogenic amines. The activities for biogenic amines, diamines and polyamines were in a constant ratio throughout the purification process. Biogenic amines found to be substrates for the enzyme included tyramine, tryptamine, beta-phenylethylamine and histamine, with Km values of 0.12 mM, 0.26 mM, 0.30 mM and 0.76 mM respectively. Octopamine, 5-hydroxytryptamine and alpha-phenylethylamine were also acceptable as substrates, though to a lesser degree. The optimum pH for biogenic-amine acetylation was 7.5, and CoA was inhibitory to the process, with a Ki of 5.5 microM. N-Acetylation appears to play a major role in the amine metabolism of this trematode. We presume that acetylation represents the process by which the parasite inactivates excess amines.

Acetylation↗
PubMed1995

Fitness of amines for pseudocyclic conformation of lasalocid A.

Ionophore lasalocid A selectively transports amines across lipid membranes. The structures of amine-lasalocid complexes were calculated by a molecular mechanics technique. Four typical catecholamines were considered: serotonin, dopamine, noradrenaline and adrenaline. The fitness energy was introduced consisting of tension energies of amine and ionophore and the interaction energy between them. Four fitted complexes of the first three amines and two of the last one were found. They are characterized by interaction between lasalocid ligand oxygens and amine ammonium groups, and also between their aromatic rings. The fitness energy increase correlates well with the decrease of the transportation rate in the considered sequence of amines.

Catecholamines↗
PubMed1974

An electron microscope autoradiographic study of the neuronal and extraneuronal localization of labeled amine in the heart of the bat after administration of tritiated norepinephrine.

The localization of labeled amine in the heart of the bat after administration of tritiated norepinephrine (NE) was studied by means of electron microscope autoradiography. Monoamine oxidase was inhibited so that the distribution of amine in both neuronal (Uptake(1)) and extraneuronal (Uptake(2)) sites could be analyzed. Labeling was nonrandom in both the atrial and ventricular myocardium. The highest relative specific activity was found in neural processes which showed morphological criteria of terminal adrenergic axons. Analysis of the distribution of label around the labeled axonal varicosities indicated that the radioactive amine was more concentrated peripherally than centrally in these structures. Label was also found over cardiocytes in both atrium and ventricle. The pattern of this labeling indicated that the radioactive amine was associated with myofilaments. In the ventricle, I bands were most heavily labeled, indicating a probable association of radioactive amine with thin filaments. Labeling was prevented by administration of phenoxybenzamine and decreased only in cardiocytes by normetanephrine. The nonrandom distribution of labeled amine within cardiocytes supports the view that Uptake(2) represents not only a second mechanism of inactivation of the sympathetic neurotransmitter, but may also be involved in the mediation of some of the action of NE on cardiac muscle.

Animals↗
PubMed1980

New reaction of 4-chloro-7-nitrobenzofurazan with amines at high local concentrations. Primitive enzyme models.

The fluorogenic amine reagent 4-chloro-7-nitrobenzofurazan (CNBFz) reacts with amines to give one of two products, or a mixture, depending on the concentration of amine. At low concentrations (e.g. 5 X 10(-4) M) of unprotonated amine the normal replacement of the chlorine occurs, giving lambdamax approximately 470 nm. At high concentration of unprotonated amine (e.g. 0.5 M), a new product, lambdamax approximately 380 nm, is produced. At intermediate concentrations, both products are seen. These results were obtained with aqueous ammonia, methylamine and butylamine, and with butylamine in dry hexane. The 380 nm product also is obtained with high local concentrations of amines, such as with [lys]n at pH 8.5-10 and micellar dodecylamine at pH 9.5. These results are suggested to be analogous to those of very primitive proto-enzyme systems, by which clusters of small molecules can produce quantitative changes in "metabolism". Reaction of CNBFz with gelatin gave qualitative evidence for cross-linking.

4-Chloro-7-nitrobenzofurazan↗
PubMed1977

Evoked efflux of 3H-bretylium by sympathomimetic amines from the rat vas deferens in vitro.

The efflux of 3H-bretylium in rat vas deferens in vitro evoked by a number of sympathomimetic amines was examined. The tissue was preloaded with 3H-bretylium (2 x 10(-7) M) and the efflux of bretylium to the incubation medium in the presence of the amines during 20 min, was determined. The efflux evoked by (+)-amphetamine was almost abolished at 0 degrees and by desipramine. The dose response curves showed that some of the amines at high concentrations markedly antagonized their own effect. It could be demonstrated that (+)-amphetamine and N-methylamphetamine at a high concentration also antagonized the efflux evoked by low external Na+ concentrations and it is suggested that this effect is produced by inhibition of the outward transport of bretylium through the neurone membrane. The structure activity relationship obtained shows that the non-hydroxylated amines are most potent in evoking bretylium efflux and that the potency diminished with the number of hydroxyl groups. The tertiary amine analogue of amphetamine is less active and the quaternary derivative much less active than amphetamine and N-methylamphetamine. A hydroxyl group at 3-position gives a somewhat higher potency than that at 4-position. This structure activity relationship is similar to that previously reported for the sympathomimetic amines in reversing the adrenergic neurone blockade for bretylium and it is proposed that this reversal is induced by the reduction of the intraneuronal concentration of bretylium as a result of the evoked efflux.

Amphetamine↗
PubMed1978

Accumulation of amines by rabbit erythrocytes in vitro.

1. Accumulation of noradrenaline (NA), 5-hydroxytryptamine (5HT) and tyramine by rabbit erythrocytes was measured at 37 degrees C in vitro. 2. Of the amines used only NA was broken down during incubation. This was a result of intracellular catechol-O-methyl transferase activity. 3. NA and 5HT entered the red cells by similar processes which were temperature-sensitive (cooling to 0 degrees C inhibited accumulation) and had saturation kinetics. The entry of NA was partially stereospecific; the (-)-isomer accumulated twice as fast as did (+)-NA. 5HT and NA competed for entry. Tyramine entry was unaffected by cooling, was not saturable and did not affect the entry of either NA or 5HT. NA and 5HT entered the erythrocytes at rates which were proportional to their lipid solubilities. 4. Metabolic inhibitors had no effect on amine transport. Inhibitors of amine transport in other tissues produced only small non-specific reductions of NA accumulation in the red cells. 5. Amine accumulation was a symmetrical process (no amine was retained by the red cells if the concentration gradient was reversed). It is concluded that NA and 5HT enter the cells by facilitated diffusion. The entry of NA and 5HT displayed countertransport, an additional feature of facilitated diffusion. 6. The relationship between the physical properties of the amines and the routes by which they entered the erythrocytes is discussed.

Animals↗
PubMed1967

Biogenic amines and emotion.

The studies discussed here have shown a fairly consistent relationship between the effects of drugs on biogenic amines, particularly norepinephrine, and affective or behavioral states. Those drugs which cause depletion and inactivation of norepinephrine centrally produce sedation or depression, while drugs which increase or potentiate brain norepinephrine are associated with behavioral stimulation or excitement and generally have an antidepressant effect in man (Table 1). From these findings, a number of investigators have formulated the concept, designated the catecholamine hypothesis of affective disorders (6), that some, if not all, depressions may be associated with a relative deficiency of norepinephrine at functionally important adrenergic receptor sites in the brain, whereas elations may be associated with an excess of such amines. It is not possible either to confirm or to reject this hypothesis on the basis of currently available clinical data. Although there does appear to be a fairly consistent relationship between the effects of pharmacological agents on norepinephrine metabolism and on affective state, a rigorous extrapolation from pharmacological studies to pathophysiology cannot be made. Confirmation of this hypothesis must ultimately depend upon direct demonstration of the biochemical abnormality in the naturally occurring illness. It should be emphasized, however, that the demonstration of such a biochemical abnormality would not necessarily imply a genetic or constitutional, rather than an environmental or psychological, etiology of depression. Whereas specific genetic factors may be of importance in the etiology of some, and possibly all, depressions, it is equally conceivable that early experiences of the infant or child may cause enduring biochemical changes and that these may predispose some individuals to depressions in adulthood. It is not likely that changes in the metabolism of the biogenic amines alone will account for the complex phenomena of normal or pathological affect. Whereas the effects of these amines at particular sites in the brain may be of crucial importance in the regulation of affect, any comprehensive formulation of the physiology of affective state will have to include many other concomitant biochemical, physiological, and psychological factors. Although in this review of the relationship of biogenic amines to affective state relatively little has been said concerning the intricate set of environmental and psychological determinants of emotion, the importance of these factors must be stressed. The normally occurring alterations in affective state induced by environmental events is well known to all, from personal experience. The interactions between such environmental determinants of affect, various physiological factors, and the complexity of psychological determinants, including cognitive factors derived from the individual's remote and immediate past experiences, have received only limited study under adequately controlled conditions. It may be anticipated, however, that this will prove to be a particularly fruitful area for future research, for only within such a multifactorial framework may one expect to understand fully the relationship of the biogenic amines to emotional state.

Antidepressive Agents↗
PubMed1993

Mast cells and biogenic amines in radiation-induced pulmonary fibrosis.

Sprague-Dawley rats were exposed to a single X-ray dose of 30 Gy over the lungs and examined at 1-wk intervals during the following 3 to 8 wk. Mast cells were counted after specific staining with toluidine blue at a low pH and the mast-cell amines, histamine (Hi) and serotonin (5-HT), were measured using high-performance liquid chromatography. Irradiation induced pneumonitis followed by pulmonary mast-cell hyperplasia and progressive fibrosis 4 to 8 wk after irradiation. By week 4, immature-looking mast cells with a few granules started to appear, followed by a gradual increase in mast cells that reached very high levels after 8 wk, up to 40 to 200 times the normal. The pulmonary Hi and 5-HT content increased concomitantly from 6 and 1 micrograms/g to a maximum of 200 and 18 micrograms/g, respectively. These high levels of amine content and mast-cell densities greatly exceed those of any normal tissue. There was a strong correlation between the Hi and 5-HT content in both normal (r = 0.87) and irradiated (r = 0.93) lung tissue, as well as between the mast-cell density and amine content after irradiation (r = 0.86), thereby indicating that both amines derived from mast cells. The Hi/5-HT quotients were much lower in both normal and irradiated lung tissue (5 and 9, respectively) than in other tissues where these amines are stored in mast cells, or in isolated peritoneal mast cells (43). This relatively higher 5-HT content in pulmonary mast cells suggests that this amine performs a specific function in the lung.

Animals↗
PubMed2004

Elevated levels of circulating trace amines in primary headaches.

BACKGROUND: Trace amines, including tyramine, octopamine, and synephrine, are closely related to classic biogenic amines. They have been hypothesized to promote migraines and other types of primary headaches, but there is no direct evidence supporting this hypothesis. METHODS: Using a multichannel electrochemical high-performance liquid chromatography system, the authors evaluated whether changes in circulating trace amines occur in subjects with migraine (with or without aura) during headache-free periods as well as in patients with cluster headache (CH) during the remission and active phases as compared with healthy control subjects. RESULTS: Plasma levels of all trace amines were significantly higher in CH patients, in both the remission and the active phases, when compared with control subjects or subjects with migraine. In addition, intraplatelet levels of octopamine, synephrine, and tyramine were higher in CH patients than in control subjects. In migraine patients, plasma levels of octopamine and synephrine were higher compared with controls, although in migraine with aura, the difference was not significant. CONCLUSIONS: Whereas the elevation of plasma trace amine levels in both migraine and CH supports the hypothesis that disorders of biogenic amine metabolism may be a characteristic biochemical trait in primary headache sufferers, the observation that such alterations are more prominent in patients with CH than migraine patients suggests that they may reflect sympathetic or hypothalamic dysfunction.

Adolescent↗
PubMedDate not supplied

Cochleotoxicity of amine groups.

It has previously been shown that polyamines are ototoxic. The relationship between the number of amine groups and ototoxicity was studied using spermine, spermidine and 1,3-diaminopropane, which are polyamines with differing numbers of amine groups. Fifty pigmented guinea pigs were studied by injecting 0.1 ml of different concentrations of spermine, spermidine or 1,3-diaminopropane intratympanically. The animals were sacrificed 4 days after the injection and the organ of Corti was studied by scanning electron microscopy. It was found that on an equimolar basis, spermine (with 4 amine groups) is more cochleotoxic than spermidine (with 3 amine groups), which is in turn more cochleotoxic than 1,3-diaminopropane (with 2 amine groups). The cochleotoxic potential of the amine groups may be a result of their cationic nature at physiological pH (7.4). This property might be part of the explanation of the ototoxicity of the aminoglycosides.

Animals↗
PubMed1990

[A method of determining trace amounts of aromatic amines in dyed cotton textiles].

A method is described for determination of trace amounts of aromatic amines present as toxic contaminants in samples of dyed cotton textiles. The study was carried out on samples of cotton textiles for children, two were dyed beige and aquamarine , one was white. A distillation-spectrophotometric method was used based on the diazo reaction of sodium nitrate + with amines and coupling reaction with alpha-naphthol. The intensity of the obtained colour was proportional to amine content in the sample. The absorbance of the colour solution was measured at 570 nm wavelength. It was shown that the tested samples contained only traces of aromatic amines calculated as aniline++--0.85-3.22 mg/kg (the acceptable amount is 40 mg/kg). The proposed method makes possible objective determination of aromatic amines in textiles, it is simple and highly effective, with detectability of the order of 10(-7) g/cm3. It may be used for amine determination in industry.

Aniline Compounds↗
PubMed1990

Primary amine drug selective electrodes with special crown ethers as neutral carriers.

Ionophores selectively sensitive to primary amines have been synthesized which display low potentiometric selectivity coefficients for K+, Na+ and NH4+ ions, secondary and tertiary amines as well as quaternary ammonium ions. These ionophores include macrocyclic polyethers with dinaphthyl subunits and azocrown ether with nitrogen donor atoms. The feasibility of these ionophores for preparing primary amine drug selective electrodes was investigated in detail. Practically usable PVC membrane electrodes sensitive to primary amine drugs, such as mexiletine, dopamine, metaraminol and tryptamine, and aliphatic primary amines have been prepared with these ionophores as neutral carriers. Direct potentiometric methods for assaying these drugs have been proposed by using the prepared electrodes. The proposed primary amine drug selective electrodes are remarkably superior to those based on ion-associates. Compared with the electrodes based on common ethers, the interference by K+, Na+ and NH4+ ions is substantially reduced. A digital simulation of the electrochemical process concerning the membrane transport was performed and some interesting conclusions have been drawn.

Dopamine↗
PubMed1989

Amine oxidase released into plasma of rats treated with hepatotoxin allyl formate.

Amine oxidase activity in plasma of rats were investigated after pretreatment with the perilobular hepatotoxin allyl formate (AF). Amine oxidase activities in plasma elevated after administration of AF 0.1 ml/kg i.p. to male rats with 1 microM and 100 microM benzylamine (Bz), 10 microM beta-phenylethylamine (beta-PEA) and 100 microM serotonin (5-HT) as substrates. But the complete inhibition of amine oxidase activities with 5-HT and beta-PEA were not observed by clorgyline as A-form MAO inhibitor and deprenyl as beta-form MAO inhibitor. The deamination of 1 microM Bz was not inhibited at high concentrations of these MAO inhibitors, while it was inhibited at low concentrations of phenelzine and semicarbazide. On the other hand, the deamination of 100 microM Bz was highly sensitive with these MAO inhibitors, while it was less sensitive with phenelzine and semicarbazide as compared with 1 microM Bz. Then, the Km values of amine oxidase in plasma of AF-administered rats with Bz as substrate were determined from Lineweaver-Burk double reciprocal plots. Two Km values for Bz of high and low Bz concentration in amine oxidase in plasma of AF-administered rats were obtained. However, this Km value of low Bz concentration was not obtained from liver mitochondria and microsomes of control rat and AF-administered rats. The Km value for beta-PEA of MAO in plasma of AF-administered rats was the same as the values of rat liver mitochondrial MAO. These results indicate that native mitochondrial MAO was released from the liver, and two or more distinct amine oxidases were released from other organs in response to AF.

Animals↗
PubMed1989

Spectroscopic characterization of secondary amine mono-oxygenase. Comparison to cytochrome P-450 and myoglobin.

Secondary amine mono-oxygenase from Pseudomonas aminovorans catalyzes the NAD(P)H- and dioxygen-dependent N-dealkylation of secondary amines to yield a primary amine and an aldehyde. Heme iron, flavin, and non-heme iron prosthetic groups are known to be present in the oligomeric enzyme. The N-dealkylation reaction is also catalyzed by the only other heme-containing mono-oxygenase, cytochrome P-450. In order to identify the heme iron axial ligands of secondary amine mono-oxygenase so as to better define the structural requirements for oxygen activation by heme enzymes, we have investigated the spectroscopic properties of the enzyme. The application of three different spectroscopic techniques, UV-visible absorption, magnetic circular dichroism and electron paramagnetic resonance, to study eight separate enzyme derivatives has provided extensive and convincing evidence for the presence of a proximal histidine ligand. This conclusion is based primarily on comparisons of the spectral properties of the enzyme with those of parallel derivatives of myoglobin (histidine proximal ligand) and P-450 (cysteinate proximal ligand). Spectral studies of ferric secondary amine mono-oxygenase as a function of pH have led to the proposal that the distal ligand is water. Deprotonation of the distal water ligand occurs upon either raising the pH to 9.0 or substrate (dimethylamine) binding. In contrast, the deoxyferrous enzyme appears to have a weakly bound nitrogen donor distal ligand. Initial spectroscopic studies of the iron-sulfur units in the enzyme are interpreted in terms of a pair of Fe2S2 clusters. Secondary amine mono-oxygenase is unique in its ability to function as cytochrome P-450 in activating molecular oxygen but to do so with a myoglobin-like active site. As such, it provides an important system with which to probe structure-function relations in heme-containing oxygenases.

Circular Dichroism↗
PubMed1982

Covalent modification of fourth component of human complement with primary amines. Binding studies with metastable fragment C4b and with C4.

A C4-dependent hemolytic complement assay and competitive binding assays with [1,4(n)-3H]putrescine or [14C]methylamine were used to determine the structural preferences of C4 and of metastable C4 for covalent modification with a series of alkyl primary amines. The pKa values of individual amines did not correspond with their ability to inactivate the hemolytic function of C4. The rank order of effectiveness did correlate with the molecular weight and conformation of the organic amines tested. In contrast to results with C4, metastable C4b displays a general increased susceptibility for modification by C3 and C4 alkyl amines. However, C4b exhibits a distinct preference for diamines, putrescine and 1,3-diaminopropane, over monoamines of the same alkyl chain length, s-butylamine and n-propylamine. Taken together, these studies provide the first direct evidence for a conformational change in the thioester region of C4 upon proteolytic activation to metastable C4b. A model is proposed to explain the results of competitive binding experiments with metastable C4b in terms of two binding sites for amines on C4b, the presumptive thioester and a second site such as the free side chain carboxyl group of glutamic acid. It is suggested that all amines except methylamine bind preferentially to the latter site; once bound, only diamines would still be capable of mounting a nucleophilic attack on the thioester bond with the second amino group.

Carbon Radioisotopes↗