Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is proposed that all peptide hormones and releasing factors are biosynthesized in the form of precursor molecules which are biologically inactive. Enzymic activation may take place by hydrolytic cleavage to release a terminal COOH group or by transmidation to form a COOH-terminal amide. Studies with pituitary prohormones and hormones are providing data that support this hypothesis. Evidence has been obtained that the 91 residue beta-lipotropin (beta-LPH) is the prohormone of beta-melanotropin (beta-MSH). The specificity of the pituitary enzymes involved in release of the hormone was demonstrated by the isolation of five constituent fragments of LPH, which were obtained in homogeneous form from the pituitary gland of the pig. The enzymes have specificities similar to trypsin and carboxypeptidase B; carboxypeptidase A and aminopeptidase activities do not appear to be involved. Mild digestion of beta-LPH by trypsin in vitro has confirmed the susceptibility of the peptide bond on the carboxy side of the paired basic residues at positions 59 and 60, adjacent to the COOH-terminus of beta-MSH, and tryptic digestion of a model peptide demonstrated the same specificity. The paired basic residues at positions 39 and 40 adjacent to the NH2-terminus of beta-MSH were more resistant to tryptic attack, both in LPH and in a model peptide. In the gland it is apparent that LPH is cleaved on the carboxy side of the paired lysyl residues at positions 39 and 40, whereas in the synthetic peptide cleavage takes place in between these residues. The activating enzyme may differ from trypsin; alternatively, explanation may be found in the conformation of the prohormone. Prediction of secondary indicates that both pairs of basic residues lie adjacent to beta-bends on the surface of the molecule and occupy sites accessible to enzymic attack. It seems likely that alpha-MSH and corticotropin (ACTH) share a common pro hormone. The release of ACTH could involve cleavage of a -Gly-Ser- bond in the prohormone to expose the NH2-terminus of the hormone. With alpha-MSH, a concerted acetylation and cleavage may take place to form the N-acetylserine residue; the COOH-terminus may be released as an amide by direct transamidation of a -Val-Gly- bond in the prohormone. Release of either hormone would be accompanied by the release of contiguous fragments of the prohormone. We have isolated two novel polypeptides from pig pituitary in substantial quantity and have determined the primary structures. They may represent fragments of a prohormone to alpha-MSH or ACTH.
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PMID:Prohormones of beta-melanotropin (beta-melanocyte-stimulating hormone, beta-MSH) and corticotropin (adrenocorticotropic hormone, ACTH): structure and activation. 18 Dec 27

Met- and leu-enkephalin contents in midbrain (including hypothalamus) and striatum of rats were determined by radioimmunoassay after bestatin (racemate) injection (200 g, i.c.v.). It was found that bestatin administration influenced the midbrain met-enkephalin content, values and directions of the changes observed being dependent upon the time after the injection. The data obtained confirm the participation of aminopeptidase in enkephalin inactivation and present evidence for the possibility of regional variations of enkephalin catabolism pathways in the brain.
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PMID:[The effect of the aminopeptidase inhibitor bestatin on the enkephalin level in the rat brain]. 208 25

The effects of the intrathecal injection of thiorphan (an inhibitor of enkephalinase inhibitor), bestatin (an inhibitor of aminopeptidase), desipramine (an inhibitor of the uptake of noradrenaline) and fluoxetine (an inhibitor of the uptake of serotonin) on the antinociception induced by beta-endorphin and morphine, administered intracerebroventricularly, were studied in male ICR mice. Antinociceptive effects were assessed by the tail-flick and hot-plate tests. Thiorphan (16 micrograms) and bestatin (16 micrograms), injected intrathecally, potentiated inhibition of the tail-flick response, induced by beta-endorphin but not by morphine administered intracerebroventricularly, whereas desipramine (6 micrograms) and fluoxetine (6 micrograms), injected intrathecally potentiated inhibition of the tail-flick response induced by morphine, but not by beta-endorphin, administered intracerebroventricularly. Thiorphan, bestatin, desipramine or fluoxetine, given intrathecally, did not antagonize inhibition of the hot-plate response, induced by beta-endorphin or morphine administered intracerebroventricularly. The results indicate that inhibition of the tail-flick response, induced by beta-endorphin administered intracerebroventricularly, is mediated by the opioid system, but not by noradrenergic and serotonergic systems in the spinal cord. On the other hand, the inhibition of the tail-flick response, induced by morphine given intracerebroventricularly, is mediated by noradrenergic and serotonergic systems, but not by the opioid system in the spinal cord. The lack of effect of enzyme inhibitors and inhibitors of the uptake of biogenic amines intrathecally on beta-endorphin- and morphine-induced inhibition of the hot-plate response, is due to the supraspinal nature of the nociceptive hot-plate response. The present results further support the hypothesis, proposed previously, that intracerebroventricularly injected beta-endorphin and morphine elicit antinociception by activating different descending inhibitory systems.
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PMID:Intrathecal administration of thiorphan, bestatin, desipramine and fluoxetine differentially potentiate the antinociceptive effects induced by beta-endorphin and morphine, administered intracerebroventricularly. 213 87

The major cystosolic aminopeptidase (alanylaminopeptidase) was purified to homogeneity from human cerebral cortex and the specificity of its actions on a series of Leu-enkephalin-related peptides of increasing chain length was determined. In each case, only the N-terminal Tyr-Gly bond was hydrolysed. Kinetic analysis of the data revealed that the specificity constant (kcat/Km;s-1M-1) falls with increasing chain length from a maximum of 13.6 x 10(4) for Leu-enkephalin (5 residues) to 5.8 x 10(2) for dynorphin (1-13). Dynorphin 1-17, while not being degraded itself acted as a competitive inhibitor (Ki = 2.7 microM) of the degradation of smaller peptides. Beta-endorphin was not hydrolysed by analylaminopeptidase, nor did it act as an inhibitor of the enzyme.
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PMID:Specificity of action of human brain alanyl aminopeptidase on Leu-enkephalin and dynorphin-related peptides. 256 98

N alpha-acetyl-gamma-endorphin (Ac gamma E) was identified in the rat neurointermediate pituitary, based on its immunological properties, comigration with synthetic Ac gamma E on HPLC and resistance to aminopeptidase-M degradation. The peptide appeared to be the main form of gamma-endorphin (gamma E) in this tissue and in brain areas remote from the hypothalamus (hippocampus, septum, amygdala). The anterior pituitary, the hypothalamus and the thalamus contained almost exclusively the non-acetylated form of gamma E. In contrast to gamma E, Ac gamma E was completely devoid of specific affinity for brain opiate binding sites. Yet, the peptide mimicked gamma E in that it potently attenuated passive avoidance behaviour in rats, when injected topically into the nucleus accumbens. It is concluded that Ac gamma E is an endogenous neuropeptide with non-opioid biological activity. N alpha-acetylation may not merely represent a mechanism for the inactivation of opioid activities of endorphins, but rather allow the organism to select specific sets of biological activities that reside in the endorphin structure.
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PMID:N alpha-Acetyl-gamma-endorphin is an endogenous non-opioid neuropeptide with biological activity. 286 46

Since both aminopeptidases and angiotensin I-converting enzyme are reported to degrade circulating enkephalins, we have examined the degradation of low-molecular-weight opioid peptides by a vascular plasma membrane-enriched fraction previously shown to contain both angiotensin I-converting enzyme (EC 3.4.15.1) and aminopeptidase M (EC 3.4.11.2). Except for an enkephalin analog resistant to amino-terminal hydrolysis, [D-Ala2]enkephalin, the purified vascular plasma membrane preferentially degraded low-molecular-weight opioids by hydrolysis of the N-terminal Tyr-1--Gly-2 bond. Enkephalin degradation was optimal at pH 7.0 and was inhibited by the aminopeptidase inhibitors amastatin (I50 = 0.08 microM), bestatin (9.0 microM) and puromycin (80 microM). Maximal rates of hydrolysis, calculated per mg plasma membrane protein, were highest for the shorter peptides (18.3, 15.6 and 16.6 nmol/min per mg for Met5-enkephalin, Leu5-enkephalin and Leu5-enkephalin-Arg6, respectively) and decreased with increasing peptide length (0.7 nmol/min per mg for dynorphin (1-13)). No significant hydrolysis of beta- and gamma-endorphin was detected. Km values decreased significantly with increasing peptide length (Km = 72.9 +/- 2.7, 43.6 +/- 4.7 and 21.4 +/- 0.9 microM for Met5-enkephalin, Leu5-enkephalin-Arg6 and Met5-enkephalin-Arg6-Phe7, respectively). However, no further decreases were seen with even larger sequences, i.e., dynorphin(1-13). Other peptides hydrolyzed by the plasma membrane aminopeptidase (angiotensin III, kallidin and hepta(5-11)-substance P) inhibited enkephalin degradation in a competitive manner. Thus, localization, specificity and kinetic data are consistent with identification of aminopeptidase M as a vascular enzyme with the capacity to differentially metabolize low-molecular-weight opioid peptides within the microenvironment of vascular cell surface receptors. Such differential metabolism may play a role in modulating the vascular effects of peripheral opioids.
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PMID:Degradation of low-molecular-weight opioid peptides by vascular plasma membrane aminopeptidase M. 287 42

Aminopeptidase M (EC 3.4.11.2), which can degrade low molecular weight opioid peptides, has been reported in both peripheral vasculature and in the CNS. Thus, we have studied the metabolism of opioid peptides by membrane-bound aminopeptidase M derived from cerebral microvessels of hog and rabbit. Both hog and rabbit microvessels were found to contain membrane-bound aminopeptidase M. At neutral pH, microvessels preferentially degraded low molecular weight opioid peptides by hydrolysis of the N-terminal Tyr1-Gly2 bond. Degradation was inhibited by amastatin (I50 = 0.2 microM) and bestatin (10 microM), but not by a number of other peptidase inhibitors including captopril and phosphoramidon. Rates of degradation were highest for the shorter peptides (Met5- and Leu5-enkephalin) whereas beta-endorphin was nearly completely resistant to N-terminal hydrolysis. Km values for the microvascular aminopeptidase also decreased significantly with increasing peptide length (Km = 91.3 +/- 4.9 and 28.9 +/- 3.5 microM for Met5-enkephalin and Met5-enkephalin-Arg6-Phe7, respectively). Peptides known to be present within or in close proximity to cerebral vessels (e.g., neurotensin and substance P) competitively inhibited enkephalin degradation (Ki = 20.4 +/- 2.5 and 7.9 +/- 1.6 microM, respectively). These data suggest that cerebral microvascular aminopeptidase M may play a role in vivo in modulating peptide-mediated local cerebral blood flow, and in preventing circulating enkephalins from crossing the blood-brain barrier.
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PMID:Metabolism of opioid peptides by cerebral microvascular aminopeptidase M. 287 69

The effect of soman poisoning on the levels of methionine enkephalin and beta-endorphin in mice and rats were determined. Soman poisoning produced no significant effect on methionine enkephalin levels in the striatum of rats or mice or beta-endorphin levels in the pituitary gland of mice. In rats beta-endorphin levels were significantly reduced 24 hr post soman poisoning, but returned to control levels by 48 hr. In vitro, the hydrolysis of leucine enkephalin by aminopeptidase was virtually complete by 30 min and found to be the major route of degradation. The release of TYR-GLY-GLY in the presence or absence of puromycin (10 microM) was found to be low (less than or equal to 2.0%). A minor effect on TYR release in the presence of GLY-GLY-PHE-MET (50 microM) was insignificant. Preincubation of mouse striatum homogenates with soman (1 or 10 microM) did not inhibit the hydrolysis of leucine enkephalin. These results suggest that the long term antinociception following soman exposure is not due to either altered concentration of endogenous opioid-like substances or inhibition of the enzymes responsible for their degradation.
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PMID:Role of endogenous opioids in soman (pinacolyl methylphosphonofluoridate)-induced antinociception. 295 88

Vasopressin (VP)-converting aminopeptidase (VP-AP) activity and VP contents were measured in single rat pineal glands during the summer of two successive years. The peptidase activity decreased significantly in August. The lowest activity (+/- SEM) of 0.18 +/- 0.02 pmol.hour-1 was recorded on August 14, compared to the basal activity of 0.25 +/- 0.01 pmol.hour-1 in July and September of 1986. The change with similar percentage occurred in the same period of 1987. The specific activity of the enzyme in the crude homogenate, 15,000 g pellet and supernatant fraction of rat pineal glands, exhibited the same pattern of variations. The decrease in peptidase activity coincided with the previously reported dramatic rise in pineal VP content in early August which was confirmed in this series of experiments. Another peptidase, the so-called gamma-endorphin generating endopeptidase (gamma-EGE) activity, and beta-endorphin-related peptides in the pineal gland did not change in this period. The results show that the variations of pineal VP contents and VP-AP activity during summer are not general for other peptides and peptidases. The coincidence of opposite changes in VP content and VP-AP activity of the pineal gland may indicate a role of the peptidase activity to regulate the VP content.
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PMID:Changes in vasopressin-converting aminopeptidase activity in the rat pineal gland during summer: relationship to vasopressin contents. 297 42

Reactions of human beta-endorphin, corticotropin and their synthetic analogs with leucine aminopeptidase have been investigated. The results confirmed previous findings that beta-endorphin is resistant to the aminopeptidase action whereas corticotropin is not. Beta-endorphin-(1-5) is completely digested by the enzyme while beta-endorphin-(1-17) is resistant. In contrast, the NH2-terminal 7 residues in corticotropin are removed readily by leucine aminopeptidase. This is confirmed by the observation that human corticotropin-(7-38) is not hydrolyzed by the enzyme. This contrasting behavior of the two hormones toward leucine aminopeptidase may be related to differences in their conformational structures.
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PMID:Distinct behavior of beta-endorphin and corticotropin toward leucine aminopeptidase action. 299 16


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