The chemistry and functioning of the mammalian erythrocyte.

The erythrocyte is a unit of protoplasm highly specialized for the functions of O2 and CO2 transport but still containing sufficient repair systems for maintaining itself for about 120 days. The erythrocyte develops through a complex series of changes, arising from a reticular cell of the, bone marrow and differentiating into an actively synthesizing and dividing nucleated cell. After a time the cell stops dividing, the nucleus begins to degenerate and a differentiation takes place in the cytoplasm, the complex mixture of cytoplasmic proteins including mitochondria being replaced almost but not completely by a single kind of protein, namely, hemoglobin. The functions of several of the anatomic features of the hemoglobin molecule are considered. The hemoglobin molecule has a molecular weight of 68,000 with 4 planar heme units which lie parallel to each other, two being on the proximal and two on the distal surface of the globin. The globin appears to be made up of 4 polypeptide layers with the planar heme units lying perpendicular to the polypeptide layers. The heme units possess a resonating ring structure which stabilizes the unit. The two vinyl groups on the periphery of the heme appear to be necessary if an iron atom is to be inserted into the newly formed protoporphyrin ring. The two ionized propionic acid groups also at the periphery of the heme, appear to be required for orienting and attaching the heme unit to two strongly basic groups of the globin, possibly guanidine groups of arginine. The attachment of the iron of heme is postulated to be to an imidazole nitrogen of a histidine residue of the globin. This latter attachment is by itself a weak bonding but is stabilized not only by the coulombic attraction of the ionized propionic acid groups but also by the Van der Waals forces between the globin and the planar resonating porphyrin. The attachment of the iron to the imidazole group endows the iron of the heme with the property of combining with O2 reversibly, the addition of O2 being connected with a pairing of all the unpaired electrons in the complex. Probably, as a consequence of this pairing of electrons, the O2 does not act as an oxidant as it would if the special iron link to globin were destroyed. The iron of the heme is bound to 6 atoms or atom groups. It binds 4 nitrogens of the protoporphyrin in the plane of the ring. Below the plane of the ring it binds one nitrogen of the imidazole group, and above the plane of the ring it may then bind O2 reversibly. The second nitrogen of the imidazole group is postulated to change its ionization with a change of oxygenation of the hemoglobin; this change in ionization makes possible the conversion of some 50 per cent of the CO2 transported in the blood to bicarbonate ion, without appreciably changing the pH of the blood. A zinc protein, carbonic anhydrase, is present in the erythrocytes to catalyze the normally slow hydration-dehydration of the CO2-H2CO3 system. How this non-nucleated erythrocyte is maintained in a functional state for a life span of 120 days is poorly understood. The erythrocyte has a very low O2 utilization which is compatible with the fact that the mitochondnia, which are believed to be the seat of cytochrome oxidase activity, are absent. However, there is present a rather complete glycolytic system which appears to play a major role in the metabolic life of the mature erythrocyte. Hemoglobin is slowly converted in the intact erythrocyte to ferric hemoglobin, i.e., methemoglobin. The methemoglobin is reduced back to the functional ferrous form by reduced diphosphopyridine nucleotide arising during glycolysis. Riboflavin enzymes appear to act as the intermediators between reduced DPN and methemoglobin. The pyridine and flavine enzymes which are slowly undergoing hydrolysis are regenerated by adenosine triphosphate produced in glycolysis. Catalase is present, probably to protect the heme units of hemoglobin against H2O2, the hemes being especially vulnerable to peroxidative attack at the methene links. ACKNOWLEDGMENTS The author wishes to acknowledge his gratefulness to L. Michaelis, E. Racker, and A. Rothen for their suggestions and criticisms.