CONTROL OF HEME SYNTHESIS BY FEEDBACK INHIBITION.

One of the most important classes of chelating agents innature are the porphyrins. A porphyrin molecule can coordinate toa metal using the four nitrogen atoms as electron-pair donors,and hence is a polydentate ligand (see Figure 1). Heme is aporphyrin that is coordinated with Fe(II) and is shown in Figure4.

T1 - The storage of globin mRNA during the inhibition of protein synthesis by heme deprivation

When the concentration of protons (H+) is low (pH9), positive charges do not form on the residues at the subunitinterfaces, so the salt bridges cannot form (right image inFigure 8). However, at pH 7, histidine residues at the subunitinterfaces (not the histidine residues that bind the heme groups)can accept an additional proton (H+), and hence becomepositively charged (Equation 1). When salt bridges form by theinteraction of these interfacial histidine residues and nearbynegatively-charged amino-acid residues, the deoxygenatedhemoglobin structure is favored, and oxygen is released (leftimage in Figure 8).


Hemoglobin synthesis in rabbit reticulocytes in vitro.

THE REGULATION OF HEMOGLOBIN SYNTHESIS AND THE PATHOGENESIS OF SOME HYPOCHROMIC ANEMIAS.

1080-1082 ()In a cell-free system of pigeon erythrocyte nuclei high concentrationsof oxygen inhibit globin synthesis because of the inhibition of hemesynthesis, which is required for globin synthesis.


Function and Synthesis of Hemoglobin

An adult at rest consumes the equivalent of 250ml of pure oxygen per minute. This oxygen is used to provideenergy for all the tissues and organs of the body, even when thebody is at rest. The body's oxygen needs increase dramaticallyduring exercise or other strenuous activities. The oxygen iscarried in the blood from the lungs to the tissues where it isconsumed. However, only about 1.5% of the oxygen transported inthe blood is dissolved directly in the blood plasma. Transportingthe large amount of oxygen required by the body, and allowing itto leave the blood when it reaches the tissues that demand themost oxygen, require a more sophisticated mechanism than simplydissolving the gas in the blood. To meet this challenge, the bodyis equipped with a finely-tuned transport system that centers onthe metal complex heme.

the synthesis of the heme portion of …

AB - Diamond Blackfan anemia (DBA) and myelodysplastic syndrome (MDS) with isolated del(5q) are severe macrocytic anemias; although both are associated with impaired ribosome assembly, why the anemia occurs is not known. We cultured marrow cells from DBA (n = 3) and del(5q) MDS (n = 6) patients and determined how heme (a toxic chemical) and globin (a protein) are coordinated. We show that globin translation initiates slowly, whereas heme synthesis proceeds normally. This results in insufficient globin protein, excess heme and excess reactive oxygen species in early erythroid precursors, and CFU-E (colony-forming unit-erythroid)/proerythroblast cell death. The cells that can more rapidly and effectively export heme or can slow heme synthesis preferentially survive and appropriately mature. Consistent with these observations, treatment with 10 mM succinylacetone, a specific inhibitor of heme synthesis, improved the erythroid cell output of DBA and del(5q) MDS marrow cultures by 68 to 95% (P = 0.03 to 0.05), whereas the erythroid cell output of concurrent control marrow cultures decreased by 4 to 13%. Our studies demonstrate that erythropoiesis fails when heme exceeds globin. Our data further suggest that therapies that decrease heme synthesis (or facilitate heme export) could improve the red blood cell production of persons with DBA, del(5q) MDS, and perhaps other macrocytic anemias.

Heme and globin synthesis control: observations in vivo …

This is a molecular model of hemoglobin with the subunits displayed in the ribbon representation. A ribbon representation traces the backbone atoms of a protein and is often used to represent its three-dimensional structure. The four heme groups are displayed in the ball-and-stick representation.