[Frontiers in Bioscience 17, 1804-1815, January 1, 2012]

Processing-independent analysis of peptide hormones and prohormones in plasma

Jens Peter Goetze1, Ingrid Hunter1,2, Solvej Koelvraa Lippert1, Linda Bardram3, Jens Frederik Rehfeld1

1Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark, 2Department of Small Animal Clinical Sciences, University of Copenhagen, Denmark, 3Department of Gastrointestinal Surgery, Rigshospitalet, Copenhagen, Denmark

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. The posttranslational phase of gene expression
3.1. Endoproteolytical cleavage
3.2. Exoproteolytic trimming
3.3. Amino acid derivatizations
4. Gut and heart: examples of posttranslational processing
4.1. Gastrin
4.2. Chromogranin
4.3. Cardiovascular peptides
5. Processing-independent analysis (PIA) - or how to quantitate proteins irrespective of the degree and nature of the posttranslational processing
6. Pitfalls of PIA measurements
7. Two examples of the clinical use of PIA measurements
7.1. Progastrin
7.2. ProBNP
8. Perspective
9. References

1. ABSTRACT

Peptide hormones are post-translationally matured before they reach a structure in which they can fulfill their biological functions. The prohormone processing may encompass a variety of endoproteolytic cleavages, N- and C-terminal trimmings, and amino acid derivatizations. The same prohormone can be variably processed in different cell types and, in addition, diseased cells often change the processing of a given precursor. The translational process is often either increased or decreased in diseased cells, which renders the ensuing modifications of the prohormone incomplete. Consequently, a variable mixture of precursors and processing-intermediates accumulates in plasma. In order to exploit disturbed posttranslational processing for diagnostic use and at the same time provide an accurate measure of the translational product, a simple analytical principle named "processing-independent analysis" (PIA) was designed. PIA-methods quantitate the total mRNA product irrespective of the degree of processing. PIA-methods have now been developed for a number of prohormones and proteins, and their diagnostic potential appears promising in diagnosis of cardiovascular disease and in several malignancies.