Hämoglobinprotein (Maus)

HEMOGLOBINS WITHIN THE GLOBIN-HEM FAMILY

Hemoglobins were originally discovered as abundant proteins in red blood cells of mammals and other vertebrates with jaws (gnathostomes) that reversibly bind and release oxygen. The major hemoglobin in adult humans, hemoglobin A, is a heterotetramer composed of two α-globin and two β-globin polypeptides, each with an associated heme group. These are encoded by the duplicated  HBA1  and  HBA2  genes or by the  HBB  gene.

• Hemoglobins are only produced in erythroid cells, where they are the main protein. Composed of multiple subunits, hemoglobin cooperatively binds oxygen in the lungs, transports the oxygen through the blood, and releases it in peripheral tissues to support oxidative metabolism.
• The heme molecule contains an iron atom (Fe) in the reduced state (iron or +2 oxidation state) and five of the six coordination sites of Fe are occupied, four by the porphyrin ring and one by the „proximal“ histidine (His) of the surrounding globin polypeptide . The sixth coordination site is reversibly bound by oxygen. Oxygen is loaded, transported, and unloaded onto hemoglobin without chemical (covalent) change to either the oxygen or the heme group, and the iron in the heme group remains in the reduced state.
• This is in contrast to the known role of many heme proteins, myoglobin (encoded by the  MB  gene) is a related, monomeric heme-linked globin protein found predominantly in skeletal and cardiac muscle. The Fe in heme is five-coordinate. It has long been described as an oxygen storage protein and facilitates the diffusion of oxygen to the mitochondria (  Wittenberg and Wittenberg 1987 ).
• Additional heme-containing globins were discovered by searching the wealth of information contained in the sequence of the human genome and transcripts made from it. Cytoglobin encoded by the  CYGB  gene  is found in many tissues (  Burmester et al. 2002  ;  Trent and Hargrove 2002  ), in sharp contrast to the strictly tissue-specific expression patterns of hemoglobin and myoglobin genes. The most distantly related globin found in the human genome is neuroglobin, which   is encoded  by NGB ( Burmester et al. 2000  ).
• Its mRNA is abundant in brain tissue but is also present in many other tissues. It is related to invertebrate nerve globins , indicating that an ancestral gene was present more than 800 million years ago, before the divergence of vertebrates and invertebrates. In contrast to the five-coordinate heme complex in hemoglobins and MB, heme forms a six-coordinate complex with both NGB and CYGB, with two His residues, designated proximal and distal, coordinated to Fe. Ligands such as oxygen and nitric oxide compete with the distal His for binding, but despite this, NGB and CYBG still have high affinity for the ligands.
• These two hexacoordinate heme-globins have been implicated in nitric oxide metabolism, with CYGB showing nitric oxide dioxygenase activity that converts nitric oxide to nitrate (  Oleksiewicz et al. 2011  ), and NGB showing nitrite reductase activity to form Nitric oxide shows (  Tiso et al. 2011  ). ). The latter activity has also been found for myoglobin (  Hendgen-Cotta et al. 2008  ) and deoxy-hemoglobin ( Gladwin and Kim-Shapiro 2008 ). Physiologically, nitrite reductase activity could provide a means of producing nitric oxide under hypoxic conditions, the signaling of which could regulate mitochondrial respiration and protect tissues (nerves by NGB, heart muscle by MB) from damage under ischemic conditions (  Dietz 2011  ).
• A role for CYGB in oxygen-requiring reactions such as hydroxylation has not been ruled out. These proposed enzymatic roles in nitric oxide and other metabolism may derive from functions performed by ancestral hemoglobins in primordial life.

The five types of globin genes listed in Figure 1 are located on five different chromosomes:  HBA1  and  HBA2  at chromosome position 16p13.3,  HBB  at 11p15.4,  MB  at 22q12.3,  CYGB  at 17q25.1 and  NGB  at 14q24.3. 

MB  ,  CYGB  and  NGB  are present as single copy genes while  HBB  and  HBA  s are present in clusters with multiple related genes. All genes consist of at least three exons separated by two introns. Although the introns differ dramatically in size, they are in homologous locations. CYGB  and  NGB  _genes each have an extra exon. It has been suggested that preservation of intron position in vertebrate globin genes facilitates exon shuffling during protein evolution. However, intron positions in globin genes differ considerably outside of vertebrates, suggesting that the conservation of intron position may simply reflect an ancestral state that has not changed during vertebrate evolution.

Species in an early divergent branch of vertebrates, the cyclostomes (represented by hagfish and lampreys), also use a heme-containing globin for oxygen transport, but surprisingly it is more closely related to CYGB than to the gnathostome hemoglobins. This suggests that the oxygen transport function of heme-containing globins arose through independent, convergent evolution in the two major vertebrate branches. In cyclostomes, oxygen transport appears to be derived by co-option of the widely expressed  CYGB  gene.