Hemoglobin as a source of endogenous bioactive peptides: The concept of tissue‐specific peptide pool

Abstract

Scattered literature data on biologically active hemoglobin-derived peptides are collected in the form of tables. Respective structure-functional correlations are analyzed and the general conclusion is reached that hemoglobin fragments must have a profound physiological function. Evidence is presented that generation of hemoglobin fragments starts inside the erythrocytes. At that stage alpha- and beta-globin chains of hemoglobin predominantly give rise to relatively long peptides containing ca. 30 amino acid residues. The primary proteolysis is followed by the next degradation step coupled with excretion of newly formed shorter peptides form red blood cells. Both the primary and the secondary proteolysis products are subjected to further stepwise C- and N-terminal chain shortening, giving rise to families of closely related peptides that are actually found in animal tissue extracts. The possible sites of primary proteolysis are compared with the positions of the exposed secondary structure elements within the monomeric alpha- and beta-globins as well as the tetrameric hemoglobin. Two tentative schemes are proposed for hemoglobin degradation, one of which starts at the globin loops exposed on the surface of the tetramer and the other, at monomeric globins where more sites are available for the action of proteases. The concept of a "tissue-specific peptide pool" is formulated, describing a novel system of peptidergic regulation, complementary to the conventional hormonal and neuromodulatory systems. According to that description, hemoglobin is only a single example, although an important one, of a vast number of functional proteins providing their proteolytically derived fragments for maintaining the tissue homeostasis.

A neuroproteomic approach to targeting neuropeptides in the brain

“…In neural tissue somatostatin is involved in the regulating control of pituitary growth hormone (GH) secretion [24,25]. Proteolytic processing of prosomatostatin produces several peptides including somatostatin-14 (S-14), somatostatin-28 (S-28), somatostatin-28 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) and antrin [26,27].…”

“…Simultaneously, there are many biologically active peptides that do not match the above mentioned characteristics of classical peptide bioregulators. Proteins are degraded after completion of their function by specific proteolytic enzymes generating fragments that can be defined as a tissue specific pool of peptides [6].…”

The Importance of Sample Handling in Neuropeptidomics

“…Most identified peptides proved to be fragments from hemoglobin. In other publications these protein fragments were described as the tissue specific pool of peptides [30]. As mentioned above, the relatively short postmortem time from decapitation to tissue preparation (3 min) was enough to produce peptides from proteins, masking the detection of neuropeptides at low concentration, and to concurrently degrade some of the neuropeptides.…”

Affinity Peptidomics Approach to Protein Detection, Quantification, and Protein Affinity Assays: Application to Forensics and Biometrics

“…Since biologically occurring peptides (whether biologically active or not) are, strictly speaking, also the products of proteolysis (e.g., insulin that is generated through partial proteolytic digestion of prepro-insulin [102] or biologically active peptides obtained through "nonspecific" proteolysis of, e.g., hemoglobin [103]), both meanings of "peptidomics" are therefore very similar in that they refer to the analysis of partially or fully proteolytically digested proteins, that is, peptides.…”