Porphyrins

Synthesis and breakdown of heme

Physiological regulation of heme synthesis

Substrate availability: iron (II) must be available for ferrochelatase.

Feedback regulation: heme is a feedback inhibitor of ALA synthase.

Subcellular localization: ALA synthase is in the mitochondria, where the

substrate, succinyl CoA, is produced. ALA synthase is synthesized in the

cytoplasm, and is transported into the mitochondria (like many other

mitochondrial proteins). Its transport across the mitochondrial membrane

may be regulated.

In erythropoietic cells, heme synthesis is coordinated with globin

synthesis. If heme is available, globin synthesis proceeds.

Effects of drugs and steroids: Remember, certain drugs and steroids

can increase heme synthesis via increased production of the rate-limiting

enzyme, ALA SYNTHASE.

Hemoglobin structure

HEMOGLOBIN Myoglobin:

Hemoglobin:

Differences in hemoglobin a myoglobin saturation by oxygen:

2,3-BPG

In addition to hydrogen ions and carbon dioxide, a very important allosteric effector

is 2,3-bisphosphoglycerate (2,3-BPG). It is a small, organic molecule that is

synthesized in red blood cells from 1,3-BPG, an intermediate in glycolysis. This

"costs" the red blood cell 1 ATP that it would have gained from converting 1,3-BPG

to 3-phosphoglycerate, but 2,3-BPG has a major and critical effect on the affinity of

hemoglobin for oxygen.

BPG affects oxygen binding affinity by binding in a small cavity at the center axis of

deoxygenated hemoglobin. In oxygenated hemoglobin, this cavity is too small to

effectively accommodate 2,3-BPG. When bound, 2,3-BPG stabilizes the

deoxygenated conformation of hemoglobin, greatly diminishing the binding of

oxygen and facilitating oxygen unloading to actively respiring tissues. At high

altitude, when the proportion of oxygen in the atmosphere is lower and hence

oxygen is harder to deliver to the tissues, the synthesis of 2,3-BPG is upregulated

significantly. It takes about 24 hours for 2,3-BPG levels to rise, and over longer

periods of time, the levels continue to increase. This is why athletes can train at

high altitudes to temporarily increase their aeorbic capacity.

Metabolism of heme, formation and

excretion of bilirubin