Blood Cells - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 74

3.5.7.2 Heme

Hemoglobin is a large protein, but its active site is a small non-proteic heme. The
heme consists of a flat porphyrin ring (4 nitrogen-containing pyrrole groups bound
by methyl bridges) based on building block porphyrin. Each heme group binds a
central ferrous iron ion (Fe 2 + ) to become the so-called hemin ( Fe 3 + -heme). 40
Heme is an iron-containing porphyrin that serves as prosthetic group in
hemeproteins. These hemeproteins are involved in: (1) oxygen binding (hemo-
and myoglobin); (2) oxygen metabolism (oxidases, peroxidases, catalases, and
hydroxylases); (3) electron transfer (cytochromes); and (4) signal transduction
(nitric oxide synthases). This signaling messenger operates in erythropoiesis, globin
synthesis, microRNA processing, and circadian rhythm regulation.
Heme binds reversibly to the nuclear receptor NR1d1 41 ahemesensorthat
coordinates the cellular clock, glucose homeostasis, and energy metabolism [ 136 ].
Transcription factor NR1d1 inhibits the circadian core clock and hepatic gluco-
neogenic gene expression.
In addition, the signaling mediator heme inactivates transcriptional repressors
such as BTB and CNC homology-1, basic leucine zipper transcription factor
BACH1.
Free heme is toxic. Therefore, its intracellular concentration is carefully re-
gulated to yield a proper supply, but avoid heme toxicity. The rate of heme
synthesis varies significantly among cell types. It is high in hepatocytes and
erythroid cells, in which large amounts of heme are needed for cytochrome-P450
and hemoglobin, respectively. Heme is degraded by heme oxygenases to biliverdin,
which is then converted to bilirubin by biliverdin reductase. Excess heme increases
the transcription of heme oxygenase-1.
In addition, intracellular heme can be exported by plasmalemmal proteins,
feline leukemia virus subgroup-C receptors (FLVCR1). This cytosolic heme export
protein carries cytoplasmic heme as well as other cyclic planar porphyrins, such as
protoporphyrin-9 and coproporphyrin, but not bilirubin. 42

40 Hemin provokes the proteasomal degradation of arginyl-transferase involved in the conjugation
of arginine to aspartate, glutamate, or oxidized cysteine in the N-end rule pathway of protein
degradation [ 135 ].
41 A.k.a. reverse erythroblastoma RevErb α .
42 Subtype FLVCR2 is a transmembrane transporter of the major facilitator superfamily that may be
involved in growth regulation and calcium exchange [ 137 ]. Proliferation and motility of vascular
endothelial cells during angiogenesis, which are Ca 2 + -dependent events, require interaction of
endothelial cells with the extracellular matrix and support cells such as pericytes. Mutations in
the FLVCR2 gene causes proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome
(PVHH), or Fowler syndrome, an autosomal-recessively inherited prenatal lethal disorder char-
acterized by hydranencephaly; diffuse clastic ischemic lesions with calcifications in the brain
stem, basal ganglia, and spinal cord; glomeruloid vasculopathy of the central nervous system
and retinal vessels; and a fetal akinesia deformation sequence (FADS) with muscular neurogenic
atrophy [ 138 ].