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Adeno-Associated Virus-Based Delivery Systems
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Hemoglobin is a tetrameric protein formed from two dimeric polypeptides. The a globin gene cluster is located on chromosome 16 within which are located α1, α2, and the embryonic ζ. The β-globin family localizes to chromosome 11 and includes the adult δ and β, and the fetal γ4 and γB. During normal erythropoiesis, six different hemoglobin proteins are expressed. The process of coordinated expression is the process of hemoglobin switching.
Phylogeny of Normal and Abnormal Hemoglobin Genes
Published in S. K. Dutta, DNA Systematics, 2019
Hemoglobin, the principal respiratory protein in all vertebrates with the possible exception of a few Antarctic fish, is a tetrameric protein consisting of two pairs of polypeptide subunits or “chains”. By convention, one pair is referred to as the a chains and the other as the non-a chains. In most animal species, when multiple normal hemoglobin types occur, one of the chains is common to all and that commonality is the distinguishing feature of the a chain. As will be discussed more extensively below, there is a marked degree of molecular homology between the a and non-a chains of a given species as well as interspecies homology between chains of like type (and obviously therefore, between unlike types as well). Each chain has associated with it a heme group which is a protoporphyrin IX group and which contains one iron atom. In functional hemoglobin, these iron atoms must be in the ferrous or 2+ oxidation state. When the iron assumes the 3+ state, the resultant hemoglobin is known as methemoglobin and is totally nonfunctional. Paradoxically then, oxygen, the principal ligand of hemoglobin, is also its worst enemy. Indeed, the internal milieu of the red cell is nearly anaerobic and one of the functions of the globin chain is the protection of the heme iron from oxidation.
Type 2 Diabetes in Childhood
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
In normal states, insulin binds to its receptor, a tetrameric protein that consists of two extracellular α subunits and two transmembrane β subunits that are joined by disulfide bonds. Binding to the extracellular receptor induces a conformational change and leads to increased tyrosine kinase activity of the β subunits. Increased kinase activity of the receptor enables recruitment and activation of intracellular substrates, with the insulin receptor substrate (IRS) family of proteins the most well described (Figure 14.1). IRS proteins act as scaffolds to bind other intracellular substrates involved in insulin-mediated activity, including PI3-kinase (PI3K). Recruitment and activation of PI3K leads to generation of phosphatidylinositol (3,4,5)-triphosphate (PIP3), which then recruits Akt to the plasma membrane [5]. Activated Akt is involved in multiple downstream processes and is thought to be the major mediator of insulin action.
Full-length recombinant antibodies from Escherichia coli: production, characterization, effector function (Fc) engineering, and clinical evaluation
Published in mAbs, 2022
mAbs are soluble serum glycoproteins, approximately 150 kilodalton (kDa) in size, and are secreted from terminally differentiated B cells in their natural environments. Each mAb molecule is composed of two identical heavy chains (HCs) and two identical light chains (LCs), with each HC featuring one variable (VH) and three constant (CH1–CH3) domains, and each LC featuring one variable (VL) and one constant (CL) domain (Figure 1a, 1b). The four chains assemble through the formation of intermolecular disulfide bonds (Figure 1b) to produce a tetrameric protein with three functional units – two antigen-binding fragment (Fab) domains and one fragment crystallizable (Fc) domain.6,7 These structural features require a sophisticated folding apparatus, as well as an oxidizing environment for the formation of disulfide bonds. In addition, glycosylation at a conserved asparagine (Asn, N) residue of the HC is required for immune cell receptors to drive various effector functions (Figure 1a, 1b).8
Clinical and genetic characteristics of hemoglobin H disease in Iran
Published in Pediatric Hematology and Oncology, 2022
Hassan Abolghasemi, Sharareh Kamfar, Azita Azarkeivan, Mehran Karimi, Bijan Keikhaei, Fahimeh Abolghasemi, Mohammad H. Radfar, Peyman Eshghi, Samin Alavi
The hemoglobin (Hb) molecule is a tetrameric protein including two alpha and two beta subunits that are synthesized independently by 2 multigene clusters located on chromosome 16 and 11 respectively.1 Thalassemic mutations in globin genes lead to the reduced or absent synthesis of hemoglobin chains.2 Alpha-thalassemia (α) as one of the most prevalent monogenic diseases in the world especially in Southeast Asia and the Middle East,3,4 is characterized by changes in the level of α-globin gene expression due to deletions or point mutations in one or more alpha globin genes.5–7 On the other hand, according to the frequency of missed or nonfunctional α-globin genes, α thalassemia can be classified to silent alpha thalassemia (single α-gene deletion (-α/αα)), alpha thalassemia trait (two alpha gene deletions in cis (–/αα) or in trans (- α/- α)), hemoglobin H disease (Hb H) (mutations in three α-globin genes (–/-α or –/αTα) and Hb Bart’s hydrops fetalis (deletion of four α-genes (- -/- -)).8,9
The therapeutic potential of RNA regulation in neurological disorders
Published in Expert Opinion on Therapeutic Targets, 2018
Jolien Roovers, Peter De Jonghe, Sarah Weckhuysen
Hereditary amyloidosis is a heterogenous group of autosomal dominant-inherited diseases characterized by the deposit of insoluble protein fibrils in the extracellular matrix [49]. Patients typically present with polyneuropathy, carpal tunnel syndrome, autonomic insufficiency, cardiomyopathy, and gastrointestinal features [49]. Mutations in transthyretin (TTR), a tetrameric protein, are the most frequent cause of hereditary amyloidosis. Mutations in the TTR gene misfold the monomer subunits, inhibiting the tetramer formation and causing aggregation into TTR amyloid fibrils (ATTR) [50]. Treatment options focus on decreasing the amount of circulating amyloidogenic protein. Patisiran is a TTR mRNA-specific siRNA formulated in lipid nanoparticles (LNPs) [51]. In a phase II clinical trial, two intravenous infusions at different doses were administered in a 3-week interval. All doses were generally well tolerated and the highest dose of 0.3 mg/kg was shown effective in reducing serum TTR protein levels by 80%. A phase III clinical trial was recently finished. The study showed improvement with patisiran relative to placebo in the primary end point of modified Neuropathy Impairment Score and additional secondary end points including sensory, motor, and autonomic neuropathy symptoms at 18 months (http://investors.alnylam.com/news-releases/news-release-details/alnylam-and-sanofi-present-positive-complete-results-apollo). A new drug application for patisiran was filed to the FDA by the end of 2017.