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PubMed1986

Degradation of low-molecular-weight opioid peptides by vascular plasma membrane aminopeptidase M.

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.

Aminopeptidases↗

PubMed1987

Metabolism of opioid peptides by cerebral microvascular aminopeptidase M.

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.

Aminopeptidases↗

PubMed1995

An aminopeptidase activity from porcine kidney that hydrolyzes oxytocin and vasopressin: purification and partial characterization.

An aminopeptidase from porcine kidney, hydrolyzing oxytocin and vasopressin in vitro, was purified by chromatography on hydroxyapatite, DEAE-cellulose and nickel ion chelate gel and gel filtration on Sephadex G-100. The enzyme appeared to be a high molecular mass (M(r) 105,000) monomeric protein. It was sensitive to inhibition by metal chelator, o-phenanthroline. Cobalt ion and sulfhydryl activator, 2-mercaptoethanol, had activating effects, while p-chloromercuribenzoate, amino acids with large hydrophobic side chains, L-cystine and aminopeptidase inhibitors, bestatin and amastatin, had inhibitory effects on the enzyme activity. The enzyme hydrolyzed several aminoacyl p-nitroanilides, and had the highest specificity against S-benzyl-L-cysteine p-nitroanilide. The properties of the enzyme were distinct from those of well-characterized leucyl aminopeptidase (EC 3.4.11.1), membrane alanyl aminopeptidase (EC 3.4.11.2) and primate placental cystinyl aminopeptidase (EC 3.4.11.3).

Aminopeptidases↗

PubMed1984

Comparative studies on the leucine aminopeptidase activity of different types of leukocytes.

The distribution of the leucine aminopeptidase activity among different types of leukocytes in a few animals was examined. In guinea-pig, the enzyme activity was detected in all cell types examined but its activity per cell was diverse among leukocytes, i.e. neutrophils and monocyte-macrophage cell lines, so-called "professional" phagocytes, showed higher enzyme activity than other types of leukocytes, lymphocytes and eosinophils. The same distribution pattern of leucine aminopeptidase activity as that in guinea-pig was also observed among leukocytes in human, rat and mouse. When leukocytes were modified with a poorly permeant reagent, diazotized sulfanilic acid to examine the subcellular localization of leucine aminopeptidase in leukocytes, the leucine aminopeptidase activity of the cells was inhibited by 50% without the inhibition of lactate dehydrogenase, a soluble cytoplasmic enzyme, in various types of leukocytes from all animals used here. The possibility was suggested from these observations that higher leucine aminopeptidase activity is distributed on the cell surface of "professional" phagocytes.

Animals↗

PubMed1992

Partial release of aminopeptidase N from larval midgut cell membranes of the silkworm, Bombyx mori, by phosphatidylinositol-specific phospholipase C.

1. The membrane anchor of aminopeptidase N associated with larval midgut cell membranes of the silkworm, Bombyx mori, was investigated by using phosphatidylinositol-specific phospholipase C (PIPLC) and proteases. 2. Aminopeptidase N, which was virtually all localized in the brush border membrane, was solubilized by PIPLC but not by papain or trypsin. 3. Detergent-solubilized amphiphilic aminopeptidase N was converted into a hydrophilic form by PIPLC but not by papain. 4. Either of these effects of PIPLC on aminopeptidase N was maximally 40%. 5. These results suggest that in larval midgut cells of the silkworm, B. mori, at least 40% aminopeptidase N is anchored in the brush border membrane via glycosyl-phosphatidylinositol.

Aminopeptidases↗

PubMed1992

Aminopeptidases in the circumventricular organs of the mouse brain: a histochemical study.

The localization of four membrane-bound aminopeptidases--aminopeptidase A, aminopeptidase M, dipeptidylpeptidase IV, and gamma-glutamyl transpeptidase--known as characteristic enzymes of the blood-brain barrier was studied in the microvasculature of some circumventricular organs of the mouse brain (subfornical organ, area postrema, choroid plexus, and neurohypophysis). Enzyme activities were demonstrated histochemically in chloroform-acetone-pretreated cryostat sections applying an azo-coupling method. Reactions were evaluated using light microscopy and end-point microdensitometry. The results revealed differences in microvascular enzyme pattern between circumventricular organs and regions having a blood-brain barrier. Moreover, the cytochemical picture of the circumventricular organs themselves was not uniform. Dipeptidylpeptidase IV reaction showed a strongly reduced activity in the microvessels of all studied circumventricular organs. On the other hand, aminopeptidase M seemed to be present in both the leaky and the tight capillaries. Only a low activity of aminopeptidase A was found in parts of the choroid endothelium and the subfornical organ microvasculature. gamma-Glutamyl transpeptidase could neither be detected in the capillary part of the choroid plexus nor in the neurohypophysis. We are led to conclude that at least dipeptidylpeptidase IV might be involved in special mechanisms of the blood-brain barrier.

Aminopeptidases↗

PubMed1993

Developmental changes of aminopeptidase activity in the cortex of the cat brain.

Aminopeptidase activity has been proposed as a candidate regulator of the degradation of several neuroactive peptides. In this paper, possible changes in Lys-, Arg-, Asp- and Tyr-aminopeptidase activities in the cat brain neocortex (frontal, parietal, area 17 and areas 18 and 19 as a whole) were examined during two of the first stages of the critical developmental period (15 and 30 days postbirth). Aminopeptidase activities were studied by measuring the rate of hydrolysis of the artificial substrates Lys-, Arg-, Asp- and Tyr-2-naphthylamides (fluorimetrically detected in triplicate). Lys- and Arg-aminopeptidase activities do not show significant changes between the first the second stage in any of the cortical regions assayed. On the contrary, in all the cortical structures, activity with Tyr-2-naphthylamide shows significant increase with age. In contrast, the activity of Asp-aminopeptidase shows significant decreases on the 30th day (except in area 17). It is suggested that these activities play a part in the neurochemical changes that take place during cat brain maturation.

Aminopeptidases↗

PubMed1991

Bestatin, an aminopeptidase inhibitor with a multi-pharmacological function.

Bestatin, the dipeptide N-((2S, 3R)-3-amino-2-hydroxy-4-phenyl butanyl) L-leucine is a leucine aminopeptidase and aminopeptidase-B inhibitor. It exerts a direct stimulating effect on lymphocytes (and monocytes) via its fixation on cell surface leucine-aminopeptidase, and an indirect effect on monocytes (and lymphocytes) via aminopeptidase B inhibition of tuftsin catabolism. Thus it is an immuno-modifier as shown by the Japanese and also our groups: a) immuno-modifier, especially stimulator, in normal young mice; b) immunorestorator and spontaneous tumor preventive agent in aged mice; c) immunorestorator in the elderly and in cancer patients and HIV infected subjects. It stimulates granulocytopoiesis and thrombocytopoiesis in vitro, and can restore them in vivo in myelo-hypoplastic man. The anti-aminopeptidase action of Bestatin also protects enkephalins against their catabolism, which encouraged us, with good preliminary results, to study its analgesic action and search for a preventive effect on "desaddicted" toxicomaniac relapses.

Aminopeptidases↗

PubMed2003

Aminopeptidases in visceral organs during alterations in body fluid volume and osmolality.

Enzymatic cleavage of some peptides in the local environment could be included among the mechanisms related to the regulation of hydrosaline balance. In order to examine this hypothesis, we measured representative aminopeptidase activities in visceral organs of rats after applying certain hydrosaline challenges. Decreased levels (about 30%) of particulate puromycin-insensitive-neutral aminopeptidase in the renal medulla and of soluble acid aminopeptidase in the lung were observed under hyperosmolality and hypovolemia. Decreased levels (more than 45%) of particulate type-I-pyroglutamyl aminopeptidase in the heart were observed under altered volemia. These results indicate that aminopeptidases at these anatomical locations might be involved in the regulation of body fluid volume and osmolality.

Aminopeptidases↗

PubMed1997

Purification and properties of a membrane aminopeptidase from Ascaris suum muscle that degrades neuropeptides AF1 and AF2.

We have identified on the membranes of the locomotory muscle of Ascaris suum an amastatin-sensitive aminopeptidase that hydrolyses the bioactive neuropeptides AF1 (KNEFIRF-NH2) and AF2 (KHEYLRF-NH2), by cleavage of the Lys1-Asn2 and Lys1-His2 peptide bonds, respectively. AF2 (1.2 nmol of HEYLRF-NH2 formed min[-1] (mg protein[-1])) was hydrolysed at a faster rate compared to AF1 (0.2 nmol of NEFIRF-NH2 formed min[-1] (mg protein[-1])). AF1 hydrolysis by the aminopeptidase was inhibited by the amastatin (IC50, 9.0 microM), leuhistin (IC50, 1.25 microM) but was insensitive to puromycin, indicating a similarity to mammalian aminopeptidase N. The enzyme was also inhibited by arphamenine B (IC50, 9.0 microM), (2S, 3R)-3-amino-2-hydroxy-4-(4-nitrophenyl)butanoyl-L-leucine (IC50, 8.0 microM), bestatin (IC50, 15.0 microM) and 1 mM 1-10 bis-phenanthroline. The detergent Triton X-100 solubilised enzyme had a pI of 5.0 and after 1000-fold purification by ion-exchange chromatography, appeared to have a Mr of around 240,000 by SDS-PAGE. The purified aminopeptidase had a Km of 534 microM for the hydrolysis of AF1 and cleaved Phe1 from FMRF-NH2, but was unable to hydrolyse DFMRF-NH2 or FDMRF-NH2. The aminopeptidase that we have described in this report might have a role in the extracellular metabolism and inactivation of neuropeptides acting on the locomotory muscle of A. suum.

Aminopeptidases↗

PubMed1998

A Plasmodium falciparum aminopeptidase gene belonging to the M1 family of zinc-metallopeptidases is expressed in erythrocytic stages.

A new single copy gene has been isolated from Plasmodium falciparum, by immunoscreening a genomic DNA expression library. The gene appears devoid of introns, displays the classical A + T richness and codon usage of P. falciparum genes, and is transcribed into a 4 kb mRNA in erythrocytic stages. The deduced amino acid sequence corresponds to a 1056 residue protein (122 kDa) containing the canonical HExxHx18E signature of zinc-metallopeptidase active sites of the M1 family at position 467-490, a downstream conserved tyrosine residue involved in catalysis in position 551, and the GAMEN conserved motif characteristic of aminopeptidases in the M1 family, at position 431-435. The greatest similarities were found with aminopeptidases N of Escherichia coli and Haemophilius influenza (more than 80% identical residues in the canonical signature of the active site) but significant similarities centred on the active site region exist with all other members of the M1 family such as other prokaryotic aminopeptidases, eukaryotic aminopeptidases A and N and leukotriene A4 hydrolases (40-50% identical residues in the canonical signature of the active site). A polyclonal serum raised to a synthetic peptide deduced from the gene labelled schizont proteins of 96 and 68 kDa purified to homogeneity and both displaying aminopeptidase activity, as well as cytoplasmic structures in schizont stages.

Amino Acid Sequence↗

PubMed2000

Binding of Bacillus thuringiensis delta-endotoxins Cry1Ac and Cry1Ba to a 120-kDa aminopeptidase-N of Epiphyas postvittana purified from both brush border membrane vesicles and baculovirus-infected Sf9 cells.

A 120-kDa protein was purified from brush border membrane vesicles of the tortricid moth Epiphyas postvittana (Walker) based both on its activity as an aminopeptidase and the ability to bind the Bacillus thuringiensis delta-endotoxin Cry1Ac. The purified enzyme had a pI of 5.6 and was a leucine aminopeptidase, with some isoleucine, phenylalanine and tryptophan aminopeptidase activity. Further characterisation showed that the protein was also able to bind Cry1Ba. During purification, the molecular weight of the protein decreased from 120 to 115 kDa due to the loss of a glycophosphatidinyl anchor. The protein was N-terminally sequenced and, using this information and conserved regions within other insect aminopeptidase-N (APN) sequences, redundant primers were designed to amplify the aminopeptidase coding sequence from E. postvittana midgut cDNA. The predicted protein sequence from the full-length cDNA was most closely related to the APN protein sequence from Heliothis virescens (61% identity) and shared other features of insect APNs including a Zn(2+) binding site motif and four conserved cysteines. The E. postvittana was expressed in Sf9 cells using baculovirus, yielding a protein of molecular weight 130 kDa, but with unchanged N-terminal sequence. Purified recombinant protein bound both Cry1Ac and Cry1Ba by ligand blot assays. However, despite the protein being expressed on the external surface of the Sf9 cells, it bound neither Cry1Ac nor Cry1Ba in vivo.

Amino Acid Sequence↗

PubMed2001

Molecular cloning of three cDNAs encoding aminopeptidases from the midgut of Helicoverpa punctigera, the Australian native budworm.

Three cDNAs encoding aminopeptidases HpAPN1, HpAPN2 and HpAPN3, were isolated from a 5th instar larval midgut cDNA library from Helicoverpa punctigera, the Australian native budworm. The sequences recovered contain open reading frames encoding proteins of 1011, 952, and 1013 amino acids, respectively. All three proteins share the consensus zinc binding/gluzincin motif HEXXHX(18)E and the sequence GAMEN common to gluzincin aminopeptidases. Furthermore, signal peptide sequences and C-terminal hydrophobic regions preceded by three small amino acids qualifying for cleavage and GPI anchor attachment are present in all three protein sequences. Northern blotting results indicate differences in the levels of expression and developmental regulation of all three aminopeptidases. HpAPN1, HpAPN2, and HpAPN3 are more closely related to APNs from other lepidopterans than they are to each other. This report of three different aminopeptidases N in Helicoverpa punctigera adds support to a recent suggestion that at least one gene duplication has taken place in ancestral lepidopterans. The full sequences of the aminopeptidases are available at GENBANK with the following accession numbers: HpAPN1: AF217248, HpAPN2: AF217249, HpAPN3: AF217250.

Amino Acid Sequence↗

PubMed2002

Characterisation of aminopeptidase activity in scab mites (Psoroptes spp.).

Soluble and membrane-bound aminopeptidase activities were demonstrated in extracts of P. cuniculi (Delafond). Leucine aminopeptidase (LAP) activity in the soluble fraction of P. cuniculi extracts displayed substrate preference for amino acid derivatives with terminal leucine and methionine over those with acidic, basic or heterocyclic groups. P. cuniculi LAP was inhibited by leucinethiol (IC(50) = 1.4 +/- 0.4 nM), bestatin (IC(50) = 3.9 +/- 1.7 microM), Arphamenine A (IC(50) = 0.37 +/- 0.03 mM) the chelating agent 1,10-phenanthroline (IC(50) = 2.3 +/- 0.5 mM), Zn(2+), Cu(2+) Ni(2+), and Co(2+), and activated by Mn(2+) and Mg(2+). The LAP activity was visualised as a single major band after electrophoresis on native gels and eluted from a size exclusion column as a single major peak representing a molecular mass range of 85-116 kDa. Degenerate oligonucleotide primers were used to amplify short fragments of genomic DNA containing nucleotide sequence coding for the cation-binding motifs of the co-catalytic Zn(2+) binding domains of dizinc leucine aminopeptidases in both P. cuniculi and P.ovis (Hering). The major soluble aminopeptidase from these mites therefore displays most of the characteristics associated with typical cytosolic leucine aminopeptidases belonging to the M17 family of metalloproteinases.

Animals↗

PubMed1997

Purification of aminopeptidase from Australian classified barley flour.

Barley is one of the major crops cultivated in the world. A new milling system, which removes successive layers of the grain has been developed, the preparation being called a classified flour. We have detected aminopeptidase activity in the flour obtained from the near surface zone. Barley was the Weeah species cultivated in Australia. Our aim in this paper is to describe the complete purification of aminopeptidase from barley classified flour. Aminopeptidase activity was determined using L-leucine-p-nitroanilide in 10 mM sodium phosphate buffer, pH 7.0. Aminopeptidase was extracted in 20 mM sodium acetate buffer, pH 5.5. Fractions (HP-1 and HP-2) were obtained upon chromatography using an HI-propyl hydrophobic interaction column in 20 mM acetate buffer, pH 5.5, with a linear gradient of ammonium sulfate from 15 to 0% saturation after the ammonium sulfate fractionation (from 40 to 60% saturation) of the extract. The final purified preparation A-1-I-G was obtained from HP-1 by gel filtration, hydroxylapatite chromatography, diethylaminomethyl-ion exchange chromatography, and re-chromatography on a Sephacryl S-100HR gel column. It was pure as assessed by native and sodium dodecylsulfate-polyacrylamide gel electrophoreses. The specific activity of A-1-I-G was 64.8 fold that of the crude extract. A K(m) value of 0.138 mM when using L-leucine-p-nitroanilide was calculated. A-1-I-G is active over a wide pH range and has a strong affinity for its substrate. The classification process is effective as a step of enzyme purification. Also, the results with metal ions suggest that the enzyme is a metalloenzyme. It was concluded that complete purification of an aminopeptidase from barley was achieved.

Aminopeptidases↗

PubMed2002

Characterization of a cytosolic aminopeptidase from Encephalitozoon intestinalis.

Aminopeptidase activity was detected in Encephalitozoon intestinalis using a fluorometric assay. The aminopeptidase was capable of hydrolysing different amino acids bound to 7-amino-4-trifluoromethyl coumarin, with maximal activity against the amino acid, leucine. Aminopeptidase activity was localized in E. intestinalis spores and in intracellular stages. Enzymatic activity was inhibited by the traditional aminopeptidase inhibitors, bestatin and its analogue, nitrobestatin. Inhibition with the chelating agents, EDTA and 1,10-phenanthroline, suggested that the enzyme activity belongs to the metalloaminopeptidase class. Subcellular fractionation demonstrated that maximal enzyme activity was localized in the cytosolic fraction. Direct fluorogenic substrate analysis by native polyacrylamide gel electrophoresis estimated a molecular weight of 70.8 kDa. Direct fluorogenic analysis by polyacrylamide ampholyte gel electrophoresis indicated an isoelectric point of 4.8. The enzyme was both heat (> 37 degrees C) and cold (< 0 degrees C) labile with an optimal activity at pH 7.2. This is the first report characterizing a cytosolic aminopeptidase in microsporidia.

Animals↗

PubMed1992

Use of azidobestatin as a photoaffinity label to identify the active site peptide of leucine aminopeptidase.

Aminopeptidases catalyze the hydrolysis of amino acid residues from the amino terminus of peptide substrates. They are found in most cells and tissues, and their activity has been implicated in myriad fundamental biochemical and physiological processes. Nevertheless, little is known about the structure of the aminopeptidase active sites. Beef lens leucine aminopeptidase (blLAP) can be considered prototypical of many enzymes in this family of peptidases. Bestatin, [(2S,3R)-(3-amino-2-hydroxy-4-phenyl-butanoyl)-L-leucine] is a nonhydrolyzable substrate analogue of a peptide, PheLeu, which is rapidly cleaved by blLAP. Bestatin incorporates elements of the putative tetrahedral intermediate, and this results in a greater than 10(5)-fold enhancement of binding relative to analogous peptides. Bestatin is the most tightly bound inhibitor of many aminopeptidases. Bestatin was successively converted to nitrobestatin, p-aminobestatin, [3H]-p-aminobestatin, and finally [3H]-p-azidobestatin (pAB). Like bestatin, pAB is a slow binding inhibitor of LAP (Ki*, the dissociation constant for the final complex, = approximately 4 x 10(-9); Ki, the dissociation constant for the initial collision complex, = approximately 10(-8). The t1/2 for binding of 2 x 10(-8) M and 8 x 10(-8) M bestatin are approximately 60 min and approximately 38 min, respectively. pAB, nitrobestatin, bestatin, and physiological peptides appear to bind in the same site, the first three with similar avidity. In the dark, pAB and bestatin protect low concentrations of the enzyme against inactivation upon extensive dialysis. The t1/2 for photoactivation of pAB is approximately 3 s. Irradiation of blLAP for such short periods of time resulted in insignificant change in activity. blLAP which was placed in 254-nm light in the presence of pAB was inactivated significantly. Treatment of photolabeled blLAP with trypsin produces only two peptides. Autoradiography and scintillation counting indicate that the active site is in the peptide which includes residues 138-487. Treatment of the same blLAP with hydroxylamine produces two different peptides, with the active site in the peptide 323-487. This indicates that the active site is in the carboxyl-terminal one-third of the protomer. It is likely that this photoaffinity label will be useful in identifying active sites in other aminopeptidases as well.

Affinity Labels↗

PubMed1992

alpha-Keto amide inhibitors of aminopeptidases.

The design and synthesis of 3-amino-2-oxo-4-phenylbutanoic acid amides (alpha-keto amides), a new class of aminopeptidase inhibitor, are described. These compounds, illustrated by the Phe-Leu analogue 2, are effective inhibitors of arginyl aminopeptidase (Ki = 1.5 microM), cytosol aminopeptidase (Ki = 1.0 microM), and microsomal aminopeptidase (Ki = 2.5 microM). The ketone carbonyl of the alpha-keto amide was found to hydrate readily in an aqueous DMSO solution, due to the electron-withdrawing effect of the neighboring amide group. A mechanism of inhibition is proposed for the alpha-keto amides that is similar to that proposed for the structurally related aminopeptidase inhibitor bestatin and its analogues, wherein the inhibitor may interact with the S1'-S2' subsite of the enzyme rather than the S1-S1' subsite. Like bestatin, the alpha-keto amides are slow-binding inhibitors of all three enzymes.

Amides↗