FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2134722420> ?p ?o ?g. }

• W2134722420 endingPage "338" @default.
• W2134722420 startingPage "335" @default.
• W2134722420 abstract "Biomarkers in MedicineVol. 3, No. 4 EditorialFree AccessPeptide hormones and their prohormones as biomarkersJens P Goetze & Jens F RehfeldJens P Goetze† Author for correspondenceDepartment of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, DK-2100, Copenhagen, Denmark. Search for more papers by this authorEmail the corresponding author at jpg@dadlnet.dk & Jens F RehfeldDepartment of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, DK-2100, Copenhagen, DenmarkSearch for more papers by this authorPublished Online:6 Aug 2009https://doi.org/10.2217/bmm.09.29AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Figure 1. Principle in processing-independent analysis.Plasma is incubated with an endoprotease in order to produce a small peptide fragment. The fragment is then measured by standard immunoassays.The accurate measurement of peptide hormones in plasma is a hallmark of basic and clinical endocrinology. From the discovery of the peptide secretin as the first bloodborne hormone to be recognized, the biological scenario for synthesis of peptide hormones now extends beyond endocrine glands to most types of tissues, including fat, muscle and nervous tissue. Accordingly, the use of hormonal peptides and their precursors as biomarkers involve several clinical disciplines besides endocrinology, where key differences in cellular synthesis and secretion must be considered in measurement and interpretation. Proper diagnostic use requires understanding of the biogenesis of hormones, including transcriptional, post-transcriptional, translational and post-translational processing and regulation of secretion. In this article, we address aspects regarding the plasma quantitation of peptide hormones and their biosynthetic precursors. It is worth noting that failure to appreciate the biosynthetic context of a peptide system can lead to mismeasurement and, at worst, fatal clinical errors.Assay specificity is a key element in any standard validation. Although elementary, it has to be recapitulated that insufficient assessment of specificity is an issue of continuous concern. If the identification of a peptide as a biological entity is new, it may be difficult to test for specificity owing to the lack of relevant calibrator materials. Such a situation may lead researchers and diagnostic companies to document ‘lack of unspecificity’ by testing against more or less structurally related peptides. However, it is not the same thing. A troublesome example of lack of specificity has been reported for the measurement of N-terminal pro-B-type natriuretic peptide (BNP), a sensitive marker of cardiac impairment, where comparison with a gold standard, in-house radioimmunoassay disclosed that a commercially available assay completely failed to detect the peptide in plasma [1]. By contrast, assay specificity is a parameter that necessarily should not only detect one molecular form of a peptide hormone. An example is gastrin measurement for diagnosing gastrin-producing tumors (gastrinomas). In this malignancy, the biosynthetic apparatus is often able to mature only a small fraction of the prohormone to the normal end product (gastrin-17). Instead, gastrinomas secrete less processed fragments of progastrin. If the assay used for biochemical measurement is too specific for the normal physiological end product, gastrin-17, it will fail to detect some tumors, which is the major diagnostic indication for gastrin measurement [2,3]. Thus, specificity should be targeted with insight and reference to the molecular heterogeneity in health and during disease [4].Another concern regarding plasma measurement is variable endoproteolytical cleavage(s) and amino acid derivatizations. These steps in the cellular synthesis are important, not only for the bioactivity and metabolism of peptides hormones, but they also affect immunological detection and biomarker use. In fact, some biomarkers utilize biological changes in cellular processing and, thereby, report on the stimulatory demand of the endocrine cells. A classic case is proinsulin measurement, where an increased demand on pancreatic β-cells leads to increased secretion of proinsulin [5]. As a result, measurement of the proinsulin:insulin ratio becomes an index of the total peripheral insulin resistance. For other peptide hormones, a molecular shift in the secreted forms towards processing intermediates or even intact precursors has also been observed [6]. An alternative strategy in assay measurement is by-passing the variable post-translational phase and quantifying one epitope that represents all translational products. This can be achieved by incubating plasma with an endoprotease (e.g., trypsin) in order to generate a uniform ‘representative’ fragment from the precursor as well as its biosynthetic products (Figure 1). The methodology also allows for assay calibration in the absence of larger synthetic or recombinant peptides. We have applied this principle in quantitation of several propeptides [7–9] and called it processing-independent assay (PIA) [7,10].Many peptide hormones and their prohormones are subjected to amino acid derivatizations during biosynthesis. For instance, almost half of all peptide hormones undergo α-carboxyamidation, which is often essential for their bioactivity [11]. The list of post-translational amino acid derivatizations is still growing (Table 1). At present, primary protein structures are deduced from cDNA sequences. Amino acid derivatizations, however, cannot be deduced. Mass spectrometry of peptides is required to determine the degree and nature of derivatizations. Moreover, it is likely that in the coming years, mass spectrometry will reveal new amino acid modifications along with the identification of the entire human proteome. The genes encoding many of the processing enzymes responsible for the amino acid derivatizations are now being cloned, and the enzyme structure and function are being identified. As several proprotein convertases may participate in the endoproteolytic processing of mono- and dibasic cleavage sites, a certain redundancy is also observed for enzymatic amino acid derivatizations. The exact role of each derivatization is not yet fully elucidated, where some appear to protect the peptide from enzymatic degradation both before and after cellular release. Other derivatizations increase or determine the interaction with binding proteins, such as chaperones, processing enzymes and receptors. Derivatizations may also serve as intracellular signals in the molecular trafficking [12,13]. Irrespective of the functional significance of a given derivatization, it influences measurement of the protein or peptide. The methods used for measurement are most often immunochemical, and if a given epitope on the protein or peptide contains one or more derivatizations, they may determine whether or to which extent the epitope is bound to antibodies. One example of this is the BNP precursor, which was recently shown to be glycosylated and that the degree of glycosylation affects endoproteolytic maturation [13,14]. O-linked pro-BNP glycosylation occurs at residues in the midregion, where immunoassays have utilized antibodies targeted at the primary structure in this domain [15]. It is worth noting that this modification was not known until recently, despite the fact that the gene was cloned 20 years ago. If the degree of modification is well characterized, however, this could in itself be used as a biomarker if assays are targeted at precisely these epitopes. This strategy deserves to be further pursued in diagnostic practice.Taking the aforementioned aspects into account regarding the plasma measurement of peptide hormones and their precursors, it should be clear that establishing the true concentrations in plasma is often a cumbersome process. Discrepancies in concentrations between different assays are a common problem in laboratory diagnostics. Frequently, a peptide hormone is first measured in relatively high concentrations. Over time, however, accumulating information on hormone biogenesis and metabolism help assay development and, thereby, accurate measurement in plasma. A fine example in this regard is plasma measurement of cholecystokinin (CCK), a hormone secreted from the proximal gut to regulate gallbladder contraction and pancreatic enzyme secretion after a meal. The first assays reported CCK concentrations in the nanomolar range, but continuous efforts in elucidating the molecular heterogeneity and excluding interference has now established that CCK circulates in very low picomolar concentrations, under tight physiological control (Table 2). Thus, reported plasma concentrations may be subject to dramatic changes, as basic research unravels the molecular pitfalls and possibilities for assay development [16].Measurement of peptide fragments other than the bioactive end product from a prohormone can have several advantages. A simple consideration is that the bioactive end product often has a short half-life in circulation and, thus, fluctuates too much to be used for diagnostic purposes. By contrast, processing-intermediate fragments may circulate in higher and more constant concentrations owing to slower metabolism. The C-peptide from proinsulin is probably the most used prohormone fragment in this regard and, similarly, N-terminal fragments of the cardiac natriuretic peptide prohormones are likely to be useful biomarkers. One particular aspect should be emphasised in this respect, although we often use such measurement as a surrogate marker for gene expression, several prohormones have been shown to contain more than one bioactive peptide fragment with distinct physiological properties [17–20]. Thus, measurements of prohormone-derived fragments may be found not to be biomarkers in respect to their generic name, but may in fact represent new biological systems. We suspect that several new hormonally active peptides may be identified from already known prohormones in the future.Measurement of peptide hormones and their prohormones is a diagnostic field that will expand over the coming decades. From being a hallmark of endocrinology, focusing on specialized endocrine glands, most tissues have now been shown to produce and secrete hormonally active peptides that demonstrate substantial promise as biomarkers. Consequently, it will be necessary to keep focus on the elucidation of peptide biogenesis, secretion and metabolism, which should complement the diagnostic possibilities.Table 1. Post-translational modifications.Endoproteolytic cleavagesExoproteolytic trimmingsAmino acid derivatizationsDibasic sitesCarboxyamidationAcylationMonobasic sitesGlutaminyl cyclationDisulfide bridgingPost-(poly) Glu/Asp sitesN-terminal dipeptidyl cleavageγ-carboxylationPost-Phe-sites GlycosylationTri- and tetrabasic sites IsomerizationPhosphorylationSulfationOctanoylationTable 2. Cholecystokinin concentrations in normal human plasma.Assay epitopePlasma concentrations (pmol/l)Year of publication BasalMaximal Unknown<96077,0001969Unknown720001973N-terminus of CCK-33122023301973N-terminus of CCK-331862931975Unknown971231977Unknown240043001978C-terminus of CCK-338241981C-terminus of CCK-3327511982Subtraction assay<0.821982Subtraction assay<0.211982C-terminus of CCK-3311251982C-terminus of CCK-33<6301982Unknown5121983C-terminus of CCK-33391983Midregion of CCK-333101983C-terminus of CCK-3316281983C-terminus of CCK-3315221984C-terminus of CCK-336231984C-terminus of CCK-333101985C-terminus of CCK-33171985Subtraction assay14–1985C-terminus of CCK-33271986C-terminus of CCK-332271987CCK-811411988CCK-8131991C-terminus of CCK-33271992C-terminus of CCK-33151992C-terminus of CCK-33141993CCK-80.5–1995N-terminus of CCK-22121995C-terminus of CCK-12151998CCK: Cholecystokinin.Data taken from[16].Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Bibliography1 Yandle T, Fisher S, Espiner E, Richards M, Nicholls G: Validating aminoterminal BNP assays: a word of caution. Lancet353,1068–1069 (1999).Crossref, Medline, CAS, Google Scholar2 Goetze JP, Rehfeld JF: Impact of assay epitope specificity in gastrinoma diagnosis. Clin. Chem.49,333–334 (2003).Crossref, Medline, CAS, Google Scholar3 Goetze JP, Paloheimo LI, Linnala A, Sipponen P, Hansen CP, Rehfeld JF: Gastrin-17 specific antibodies are too specific for gastrinoma diagnosis but stain G-cells. Scand. J. Gastroenterol.40,596–598 (2005).Crossref, Medline, CAS, Google Scholar4 Rehfeld JF: The art of measuring gastrin in plasma: a dwindling diagnostic discipline? Scand. J. Clin. Lab. Invest.68,353–361 (2008).Crossref, Medline, CAS, Google Scholar5 Melani F, Rubenstein AH, Oyer PE, Steiner DF: Identification of proinsulin and C-peptide in human serum by a specific immunoassay. Proc. Natl Acad. Sci. USA67,148–155 (1970).Crossref, Medline, CAS, Google Scholar6 Giuliani I, Rieunier F, Larue C et al.: Assay for measurement of intact B-type natriuretic peptide prohormone in blood. Clin. Chem.52,1054–1061 (2006).Crossref, Medline, CAS, Google Scholar7 Bardram L, Rehfeld JF: Processing-independent radioimmunoanalysis: a general analytical principle applied to progastrin and its products. Anal. Biochem.175,537–543 (1988).Crossref, Medline, CAS, Google Scholar8 Paloheimo LI, Rehfeld JF: A processing-independent assay for human procholecystokinin and its products. Clin. Chim. Acta229,49–65 (1994).Crossref, Medline, CAS, Google Scholar9 Goetze JP, Kastrup J, Pedersen F, Rehfeld JF: Quantification of pro-B-type natriuretic peptide and its products in human plasma by use of an analysis independent of precursor processing. Clin. Chem.48,1035–1042 (2002).Crossref, Medline, CAS, Google Scholar10 Rehfeld JF, Goetze JP: The posttranslational phase of gene expression: new possibilities in molecular diagnosis. Curr. Mol. Med.3,25–38 (2003).Crossref, Medline, CAS, Google Scholar11 Eipper BA, Mains RE: Peptide α-amidation. Annu. Rev. Physiol.50,333–344 (1988).Crossref, Medline, CAS, Google Scholar12 Bundgaard JR, Vuust J, Rehfeld JF: Tyrosine O-sulfation promotes proteolytic processing of progastrin. EMBO J.14,3073–3079 (1995).Crossref, Medline, CAS, Google Scholar13 Semenov AG, Postnikov AB, Tamm NN et al.: Processing of pro-brain natriuretic peptide is suppressed by O-glycosylation in the region close to the cleavage site. Clin. Chem.55,489–498 (2009).Crossref, Medline, CAS, Google Scholar14 Schellenberger U, O’Rear J, Guzzetta A, Jue RA, Protter AA, Pollitt NS: The precursor to B-type natriuretic peptide is an O-linked glycoprotein. Arch. Biochem. Biophys.451,160–166 (2006).Crossref, Medline, CAS, Google Scholar15 Goetze JP, Dahlström U, Rehfeld JF, Alehagen U: Impact of epitope specificity and precursor maturation in pro-B-type natriuretic peptide measurement. Clin. Chem.54,1780–1787 (2008).Crossref, Medline, CAS, Google Scholar16 Rehfeld JF: How to measure cholecystokinin in tissue, plasma and cerebrospinal fluid. Regul. Pept.78(1–3),31–39 (1998).Crossref, Medline, CAS, Google Scholar17 Kobayashi H, Yanagita T, Yokoo H, Wada A: Pathophysiological function of adrenomedullin and proadrenomedullin N-terminal peptides in adrenal chromaffin cells. Hypertens. Res.26,S71–S78 (2003).Crossref, Medline, CAS, Google Scholar18 Steiner DF: The proinsulin C-peptide – a multirole model. Exp. Diabesity Res.5,7–14 (2004).Crossref, Medline, CAS, Google Scholar19 Holst JJ: The physiology of glucagon-like peptide 1. Physiol. Rev.87,1409–1439 (2007).Crossref, Medline, CAS, Google Scholar20 Pemberton CJ, Richards AM: Biochemistry of ghrelin precursor peptides. Vitam. Horm.77,13–30 (2008).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByState of the art of immunoassay methods for B-type natriuretic peptides: An update30 December 2014 | Critical Reviews in Clinical Laboratory Sciences, Vol. 52, No. 2Cardiac biomarker testing in the clinical laboratory: Where do we stand? General overview of the methodology with special emphasis on natriuretic peptidesClinica Chimica Acta, Vol. 443BNP in children with congenital cardiac disease: is there now sufficient evidence for its routine use?20 January 2015 | Cardiology in the Young, Vol. 25, No. 3Recent advances on natriuretic peptide system: New promising therapeutic targets for the treatment of heart failurePharmacological Research, Vol. 76Urinary osteocalcin and serum pro-C-type natriuretic peptide predict linear catch-up growth in infants15 June 2012 | Journal of Bone and Mineral Research, Vol. 27, No. 7The paradox of low BNP levels in obesity27 April 2011 | Heart Failure Reviews, Vol. 17, No. 1Circulating Forms of the B-Type Natriuretic Peptide ProhormoneB-Type Natriuretic Peptide: From Posttranslational Processing to Clinical Measurement1 January 2012 | Clinical Chemistry, Vol. 58, No. 1N-Terminal Pro–Atrial Natriuretic Peptide Measurement in Plasma Suggests Covalent Modification1 September 2011 | Clinical Chemistry, Vol. 57, No. 9Measurement of the pro-hormone of brain type natriuretic peptide (proBNP): methodological considerations and pathophysiological relevanceClinical Chemistry and Laboratory Medicine (CCLM), Vol. 49, No. 12 Vol. 3, No. 4 Follow us on social media for the latest updates Metrics History Published online 6 August 2009 Published in print August 2009 Information© Future Medicine LtdFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
• W2134722420 created "2016-06-24" @default.
• W2134722420 creator A5085229618 @default.
• W2134722420 creator A5091673364 @default.
• W2134722420 date "2009-08-01" @default.
• W2134722420 modified "2023-09-26" @default.
• W2134722420 title "Peptide hormones and their prohormones as biomarkers" @default.
• W2134722420 cites W14408915 @default.
• W2134722420 cites W1569976835 @default.
• W2134722420 cites W1972059691 @default.
• W2134722420 cites W1973167487 @default.
• W2134722420 cites W1974261541 @default.
• W2134722420 cites W1988977380 @default.
• W2134722420 cites W2000759609 @default.
• W2134722420 cites W2016870770 @default.
• W2134722420 cites W2022384226 @default.
• W2134722420 cites W2025241874 @default.
• W2134722420 cites W2080608051 @default.
• W2134722420 cites W2080749051 @default.
• W2134722420 cites W2081846189 @default.
• W2134722420 cites W2083302031 @default.
• W2134722420 cites W2086641715 @default.
• W2134722420 cites W2091518124 @default.
• W2134722420 cites W2106036385 @default.
• W2134722420 cites W2127121770 @default.
• W2134722420 cites W2157397275 @default.
• W2134722420 doi "https://doi.org/10.2217/bmm.09.29" @default.
• W2134722420 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/20477480" @default.
• W2134722420 hasPublicationYear "2009" @default.
• W2134722420 type Work @default.
• W2134722420 sameAs 2134722420 @default.
• W2134722420 citedByCount "10" @default.
• W2134722420 countsByYear W21347224202012 @default.
• W2134722420 countsByYear W21347224202013 @default.
• W2134722420 countsByYear W21347224202014 @default.
• W2134722420 countsByYear W21347224202015 @default.
• W2134722420 crossrefType "journal-article" @default.
• W2134722420 hasAuthorship W2134722420A5085229618 @default.
• W2134722420 hasAuthorship W2134722420A5091673364 @default.
• W2134722420 hasConcept C126322002 @default.
• W2134722420 hasConcept C71315377 @default.
• W2134722420 hasConcept C71924100 @default.
• W2134722420 hasConceptScore W2134722420C126322002 @default.
• W2134722420 hasConceptScore W2134722420C71315377 @default.
• W2134722420 hasConceptScore W2134722420C71924100 @default.
• W2134722420 hasIssue "4" @default.
• W2134722420 hasLocation W21347224201 @default.
• W2134722420 hasLocation W21347224202 @default.
• W2134722420 hasOpenAccess W2134722420 @default.
• W2134722420 hasPrimaryLocation W21347224201 @default.
• W2134722420 hasRelatedWork W1991634850 @default.
• W2134722420 hasRelatedWork W2010645160 @default.
• W2134722420 hasRelatedWork W2059655794 @default.
• W2134722420 hasRelatedWork W2069420617 @default.
• W2134722420 hasRelatedWork W2164661085 @default.
• W2134722420 hasRelatedWork W2171532347 @default.
• W2134722420 hasRelatedWork W2324197635 @default.
• W2134722420 hasRelatedWork W2400800471 @default.
• W2134722420 hasRelatedWork W305351029 @default.
• W2134722420 hasRelatedWork W4290257889 @default.
• W2134722420 hasVolume "3" @default.
• W2134722420 isParatext "false" @default.
• W2134722420 isRetracted "false" @default.
• W2134722420 magId "2134722420" @default.
• W2134722420 workType "article" @default.