Fetal hemoglobin

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Fetal hemoglobin protein structure

Fetal hemoglobin, or foetal haemoglobin, (also hemoglobin F, HbF, or α2γ2) is the main oxygen transport protein in the human fetus during the last seven months of development in the uterus and persists in the newborn until roughly 6 months old. Functionally, fetal hemoglobin differs most from adult hemoglobin in that it is able to bind oxygen with greater affinity than the adult form, giving the developing fetus better access to oxygen from the mother's bloodstream.

In newborns, fetal hemoglobin is nearly completely replaced by adult hemoglobin by approximately 6 months postnatally, except in a few thalassemia cases in which there may be a delay in cessation of HbF production until 3–5 years of age. In adults, fetal hemoglobin production can be reactivated pharmacologically,[1] which is useful in the treatment of diseases such as sickle-cell disease.

Overview[edit]

The oxygen saturation curve for fetal hemoglobin (blue) appears left-shifted when compared to adult hemoglobin (red) since fetal hemoglobin has a greater affinity for oxygen.

Oxygenated blood is delivered to the fetus via the umbilical vein from the placenta, which is anchored to the wall of the mother's uterus. The chorion acts as a barrier between the maternal and fetal circulation so that there is no admixture of maternal and fetal blood. Blood in the maternal circulation is delivered via open ended arterioles to the intervillous space of the chorionic plate, where it bathes the chorionic villi that carry umbilical capillary beds, thereby allowing gas exchange to occur between the maternal and fetal circulation. Deoxygenated maternal blood drains into open ended intervillous venules to return to maternal circulation. Due to the admixture of oxygenated and deoxygenated blood, maternal blood in the intervillous space is lower in oxygen than arterial blood. As such, fetal hemoglobin must be able to bind oxygen with greater affinity than adult hemoglobin in order to compensate for the relatively lower oxygen tension of the maternal blood supplying the chorion.

Fetal hemoglobin's affinity for oxygen is substantially greater than that of adult hemoglobin. Notably, the P50 value for fetal hemoglobin is lower than adult hemoglobin (i.e., the partial pressure of oxygen at which the protein is 50% saturated; lower values indicate greater affinity). The P50 of fetal hemoglobin is roughly 19 mmHg, whereas adult hemoglobin is approximately 26.8 mmHg. As a result, the "oxygen saturation curve", which plots percent saturation vs. pO2, is left-shifted for fetal hemoglobin as compared to adult hemoglobin.

This greater affinity for oxygen is explained by the lack of fetal hemoglobin's interaction with 2,3-bisphosphoglycerate (2,3-BPG or 2,3-DPG). In adult red blood cells, this substance decreases the affinity of hemoglobin for oxygen. 2,3-BPG is also present in fetal red blood cells, but interacts less efficiently with fetal hemoglobin than adult hemoglobin. This is due to a change in a single amino acid (residue 143) found in the 2,3-BPG 'binding pocket': from histidine to serine, which gives rise to the greater oxygen affinity.

Whereas histidine is positively charged and interacts well with the negative charges found on the surface of 2,3-BPG, Serine has a neutrally charged side chain at physiological pH, and interacts less well. This change results in less binding of 2,3-BPG to fetal Hb, and as a result oxygen will bind to it with higher affinity than adult hemoglobin.[2]

For mothers to deliver oxygen to a fetus, it is necessary for the fetal hemoglobin to extract oxygen from the maternal oxygenated hemoglobin across the placenta. The higher oxygen affinity required for fetal hemoglobin is achieved by the protein subunit γ (gamma), instead of the β (beta) subunit. Because the γ subunit has fewer positive charges than the (adult) β subunit, 2,3-BPG is less electrostatically bound to fetal hemoglobin compared to adult hemoglobin. This lowered affinity allows for adult hemoglobin (maternal hemoglobin) to readily transfer its oxygen to the fetal bloodstream.

Distribution[edit]

After the first 10 to 12 weeks of development, the fetus' primary form of hemoglobin switches from embryonic hemoglobin to fetal hemoglobin. At birth, fetal hemoglobin comprises 50-95% of the infant's hemoglobin. These levels decline after six months as adult hemoglobin synthesis is activated while fetal hemoglobin synthesis is deactivated. Soon after, adult hemoglobin (hemoglobin A in particular) takes over as the predominant form of hemoglobin in normal children.

Certain genetic abnormalities can cause the switch to adult hemoglobin synthesis to fail, resulting in a condition known as hereditary persistence of fetal hemoglobin (HPFH).

Structure and genetics[edit]

Most types of normal hemoglobin, including hemoglobin A, hemoglobin A2, as well as hemoglobin F, are tetramers composed of four protein subunits and four heme prosthetic groups. Whereas adult hemoglobin is composed of two α (alpha) and two β (beta) subunits, fetal hemoglobin is composed of two α subunits and two γ (gamma) subunits, and is commonly denoted as α2γ2. Because of its presence in fetal hemoglobin, the γ subunit is commonly called the "fetal" hemoglobin subunit.

In humans, the gamma subunit is encoded on chromosome 11, as is the beta subunit. There are two similar copies of the gamma subunit gene: γG which has a glycine at position 136, and γA which has an alanine. The gene that codes for the alpha subunit is located on chromosome 16 and is also present in duplicate.

Clinical significance[edit]

Treatment of sickle-cell disease[edit]

Increasing the body's production of fetal hemoglobin is used as a strategy to treat sickle-cell disease.

When fetal hemoglobin production is switched off after birth, normal children begin producing adult hemoglobin (HbA). Children with sickle-cell disease instead begin producing a defective form of hemoglobin called hemoglobin S which aggregates together and forms filaments that cause red blood cells to change their shape from round to sickle-shaped. These defective red blood cells have a greater tendency to stack on top of one another and block blood vessels. These invariably lead to so-called painful vaso-occlusive episodes, which are a hallmark of the disease.

If fetal hemoglobin remains the predominant form of hemoglobin after birth, the number of painful episodes decreases in patients with sickle-cell disease. Hydroxyurea promotes the production of fetal hemoglobin and can thus be used to treat sickle-cell disease.[1][3] The fetal hemoglobin's reduction in the severity of the disease comes from its ability to inhibit the formation of hemoglobin aggregates within red blood cells which also containing hemoglobin S. Combination therapy with hydroxyurea and recombinant erythropoietin—rather than treatment with hydroxyurea alone—has been shown to further elevate hemoglobin F levels and to promote the development of HbF-containing F-cells.[4]

References[edit]

  1. ^ a b Lanzkron S, Strouse JJ, Wilson R et al. (June 2008). "Systematic review: Hydroxyurea for the treatment of adults with sickle cell disease". Annals of Internal Medicine 148 (12): 939–55. doi:10.7326/0003-4819-148-12-200806170-00221. PMC 3256736. PMID 18458272. 
  2. ^ Berg, Jeremy M.; John L. Tymoczko; Lubert Stryer. Web content by Neil D. (2002). "10.2". Biochemistry (5. ed., 4. print. ed.). New York, NY [u.a.]: W. H. Freeman. p. Section 10.2Hemoglobin Transports Oxygen Efficiently by Binding Oxygen Cooperatively. ISBN 0-7167-3051-0. 
  3. ^ Charache S, Terrin ML, Moore RD et al. (May 1995). "Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia". The New England Journal of Medicine 332 (20): 1317–22. doi:10.1056/NEJM199505183322001. PMID 7715639. 
  4. ^ Rodgers GP, Dover GJ, Uyesaka N, Noguchi CT, Schechter AN, Nienhuis AW (January 1993). "Augmentation by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cell disease". The New England Journal of Medicine 328 (2): 73–80. doi:10.1056/NEJM199301143280201. PMID 7677965. 

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