Prohormone-substrate peptide sequence recognition by peptidylglycine α-amidating monooxygenase and its reflection in increased glycolate inhibitor potency

Morris, Kelly M.; Cao, Feihua; Onagi, Hideki; Altamore, Timothy M.; Gamble, Allan B.; Easton, Christopher J.

doi:10.1016/j.bmcl.2012.10.004

Cited by 6 publications

(4 citation statements)

References 26 publications

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“…Interestingly, salsolinol also up‐regulated PAM gene expression in sites related to oxytocin synthesis. Amidation of peptides, including oxytocin, by PAM is a post‐translational modification that is required for full biological activity . PAM is a copper‐dependent cuproenzyme found in both the anterior and posterior pituitary and hypothalamus, especially in the PVN and SON .…”

Section: Discussionmentioning

confidence: 99%

Salsolinol Up‐Regulates Oxytocin Expression and Release During Lactation in Sheep

Górski

Marciniak

Zielińska‐Górska

et al. 2016

J Neuroendocrinology

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Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) is a dopamine-derived compound present in the central nervous system and pituitary gland. Several previous studies on lactating sheep and rats have reported that salsolinol plays a crucial role in the regulation of prolactin secretion. The present study investigated the effects of salsolinol, which was infused into the third ventricle of the brain, on oxytocin expression and release in lactating sheep, 48 h after weaning of 8-week-old lambs. Serial 30-min infusions of salsolinol and vehicle were performed at 30-min intervals from 10.00 to 15.00 h. Blood samples were collected every 10 min. The supraoptic nucleus (SON), paraventricular nucleus (PVN) and posterior pituitary were collected immediately after the experiment. Expression levels of mRNAs for oxytocin and peptidylglycine α-amidating monooxygenase (PAM), the terminal enzyme in the oxytocin synthesis pathway, were measured using a real-time polymerase chain reaction. Oxytocin peptide content in the posterior pituitary was measured by an enzyme-linked immunosorbent assay, and plasma oxytocin concentration was measured by radioimmunoassay. Salsolinol treatment significantly up-regulated oxytocin and PAM gene expression in the SON (P < 0.01 and P < 0.05, respectively), PVN (P < 0.01 and P < 0.05, respectively) and posterior pituitary (P < 0.05 and P < 0.05, respectively). Oxytocin peptide content in the posterior pituitary and the area under the response curve of plasma oxytocin were significantly (P < 0.05 and P < 0.01, respectively) higher in salsolinol-treated sheep than in control animals. The present study shows for the first time that salsolinol stimulates oxytocin secretion during lactation in sheep.

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Section: Discussionmentioning

confidence: 99%

Salsolinol Up‐Regulates Oxytocin Expression and Release During Lactation in Sheep

Górski

Marciniak

Zielińska‐Górska

et al. 2016

J Neuroendocrinology

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“…It is the only known human enzyme able to catalyze α-amidation of peptides [72,[147][148][149]. The reaction is crucial for the production of a number of hormones/neurotransmitters (e.g., calcitonin, oxytocin, vasopressin, GLP-1, substance P, neuropeptide Y), and the enzyme is highly expressed in many neurons and endocrine tissues [4,72,[150][151][152][153]. The enzyme can also amidate non-proteins such as fatty acid glycines [72].…”

Section: Vitamin C-dependent Monooxygenasesmentioning

confidence: 99%

Vitamin C—Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination

et al. 2021

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Vitamin C (L-ascorbic acid) has been known as an antioxidant for most people. However, its physiological role is much larger and encompasses very different processes ranging from facilitation of iron absorption through involvement in hormones and carnitine synthesis for important roles in epigenetic processes. Contrarily, high doses act as a pro-oxidant than an anti-oxidant. This may also be the reason why plasma levels are meticulously regulated on the level of absorption and excretion in the kidney. Interestingly, most cells contain vitamin C in millimolar concentrations, which is much higher than its plasma concentrations, and compared to other vitamins. The role of vitamin C is well demonstrated by miscellaneous symptoms of its absence—scurvy. The only clinically well-documented indication for vitamin C is scurvy. The effects of vitamin C administration on cancer, cardiovascular diseases, and infections are rather minor or even debatable in the general population. Vitamin C is relatively safe, but caution should be given to the administration of high doses, which can cause overt side effects in some susceptible patients (e.g., oxalate renal stones). Lastly, analytical methods for its determination with advantages and pitfalls are also discussed in this review.

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“…One class of compounds investigated as PHM inhibitors are the glycolates, R‐CO‐O‐CH 2 ‐COOH; the R‐groups described include an acyl group (short‐ and long‐chain), a benzoyl group, a phenylacetyl‐group, an N ‐acetyl‐amino acid and N ‐acetyl‐peptides (Barratt et al, 2004; Cao et al, 2011; Katopodis & May, 1990a; Morris et al, 2012; Ping et al, 1995) (Figure 3d). The glycolates are analogues of the glycine‐extended substrates and were clear substrate analogues for consideration as inhibitors.…”

Section: Effective Phm and Pal Inhibitors Were Developedmentioning

confidence: 99%

Peptidylglycine α‐amidating monooxygenase as a therapeutic target or biomarker for human diseases

Merkler

Hawley

Eipper

et al. 2022

British J Pharmacology

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Peptides play a key role in controlling many physiological and neurobiological pathways. Many bioactive peptides require a C‐terminal α‐amide for full activity. The bifunctional enzyme catalysing α‐amidation, peptidylglycine α‐amidating monooxygenase (PAM), is the sole enzyme responsible for amidated peptide biosynthesis, from Chlamydomonas reinhardtii to Homo sapiens. Many neuronal and endocrine functions are dependent upon amidated peptides; additional amidated peptides are growth promoters in tumours. The amidation reaction occurs in two steps, glycine α‐hydroxylation followed by dealkylation to generate the α‐amide product. Currently, most potentially useful inhibitors target the first reaction, which is rate‐limiting. PAM is a membrane‐bound enzyme that visits the cell surface during peptide secretion. PAM is then used again in the biosynthetic pathway, meaning that cell‐impermeable inhibitors or inactivators could have therapeutic value for the treatment of cancer or psychiatric abnormalities. To date, inhibitor design has not fully exploited the structures and mechanistic details of PAM.

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Prohormone-substrate peptide sequence recognition by peptidylglycine α-amidating monooxygenase and its reflection in increased glycolate inhibitor potency

Cited by 6 publications

References 26 publications

Salsolinol Up‐Regulates Oxytocin Expression and Release During Lactation in Sheep

Salsolinol Up‐Regulates Oxytocin Expression and Release During Lactation in Sheep

Vitamin C—Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination

Peptidylglycine α‐amidating monooxygenase as a therapeutic target or biomarker for human diseases

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