Haptoglobin protein

In healthy individuals, the concentration of plasma proteins is constant. Diseases in organs that are involved in protein synthesis and breakdown can shift the protein pattern. For example, via cytokines (see p. 392), severe injuries trigger increased synthesis of acute-phase proteins, which include C-reac-tive protein, haptoglobin, fibrinogen, complement factor C-3, and others. The concentrations of individual proteins are altered in some diseases (known as dysproteinemias). 

These criteria are in descending order of strength. If criteria 1 and 2 hold, the rest will follow, in most—but not all—cases. Note that in the serine proteases, tertiary structure is more conserved than primary structure. Sometimes structure has been conserved through evolution, but function has changed that is, criteria 3 and 4 do not hold. For example, the binding protein haptoglobin appears to have diverged from the serine proteases. 

Be familiar with, know the function of, and know the diagnostic significance of the following plasma proteins haptoglobin, hemopexin, albumin, fibrinogen, immunoglobulins, a-1-antitrypsin, and complement. 

Figure 1. a-Carbon plot of the chain of the protein haptoglobin. Only the a-car-borts are shown to allow the folding of the chain to be seen. 

A seventh vitamin K-dependent protein, protein Z, has been isolated from plasma (123). Protein Z is closely related to the factor IX-like proteases, factors VII, IX, X and protein C, consisting of the Gla domain, the two EGF units and a single Hya residue. However, similar to the heme binding protein haptoglobin, protein Z has no associated proteolytic activity as the two of the three essential catalytic residues have been modified (123). In contrast to protein sequencing, cDNA analysis allows the prediction of the amino acid sequence of the primary translation product of the mRNA species. Post-translational modifications are not detected, but precursor structures are elucidated. The vitamin K-dependent clotting factors are synthesized as precursors with leader sequences of 38 to 46 amino... 

A number of adipokines are linked to inflammation and immunity (Fig. 1). This includes both leptin and adiponectin, and also a number of other key inflammatory proteins, particularly cytokines and chemokines [1]. The cytokines and chemokines encompass interleukin-1(3 (EL-1 (3), IL-6, DL-10, TNFa, monocyte chemoattractant protein-1 (MCP-1), and macrophage migration inhibitory factor (MIF). Other major inflammation-related adipokines include nerve growth factor (NGF), and acute phase proteins such as serum amyloid A and haptoglobin. In addition, adipocytes secrete plasminogen activator inhibitor-1 (PAI-1), which is an important thrombotic factor as well as an acute phase protein. 

These proteins are called acute phase proteins (or reactants) and include C-reactive protein (CRP, so-named because it reacts with the C polysaccharide of pneumococci), ai-antitrypsin, haptoglobin, aj-acid glycoprotein, and fibrinogen. The elevations of the levels of these proteins vary from as little as 50% to as much as 1000-fold in the case of CRP. Their levels are also usually elevated during chronic inflammatory states and in patients with cancer. These proteins are believed to play a role in the body s response to inflammation. For example, C-reactive protein can stimulate the classic complement pathway, and ai-antitrypsin can neutralize certain proteases released during the acute inflammatory state. CRP is used as a marker of tissue injury, infection, and inflammation, and there is considerable interest in its use as a predictor of certain types of cardiovascular conditions secondary to atherosclerosis. Interleukin-1 (IL-1), a polypeptide released from mononuclear phagocytic cells, is the principal—but not the sole—stimulator of the synthesis of the majority of acute phase reactants by hepatocytes. Additional molecules such as IL-6 are involved, and they as well as IL-1 appear to work at the level of gene transcription. 

Table 50-2 summarizes the functions of many of the plasma proteins. The remainder of the material in this chapter presents basic information regarding selected plasma proteins albumin, haptoglobin, transferrin, ceruloplasmin, aj-antitrypsin, aj i roglobulin, the immunoglobulins, and the complement system. The lipoproteins are discussed in Chapter 25. 

Fig. 11.9 Response curve for haptoglobin on a 96 well in line BioCD with protein A/G immobi lization. Error bars are standard deviation of 9 wells...

The vague definition offered above or rather these characteristics appear to be sufficient since no plasma protein capable of forming a strong bond with Hb is known to occur in mammalian plasma except those mucoproteins with the general biochemical properties originally accepted as characteristic of haptoglobins. 

In the later discussion of the method for measuring Hp it is considered as established that haptoglobins are the only native plasma proteins which exist or may exist in normal or pathological mammalian plasma with a HbBC above 5 mg/100 ml, i.e., the lowest capacity measurable by routine methods. It is also assumed that native haptoglobins themselves have no affinity for heme. The suggestion by Jones et al. (J14) that rabbit Hp has affinity for heme still lacks supportive evidence and can therefore not yet be accepted. 

B9. Blumberg, B. S., Allison, A. C., and Garry, B., The haptoglobins, hemoglobins and serum proteins of the Alaskan fur seal, ground squirrel and marmot.. Cellular Comp. Physiol. 55, 61 (1960). 

P5. Poulik, M. D., Interaction of transferrin, haptoglobin and other serum proteins with neuraminidase of diphtheria toxin. Clin. Chim. Acta 6, 493 (1961). 

In the 1950s, new methods of protein separation were developed that enabled the systematic study of molecular variation in many more human proteins. Starch gel electrophoresis allowed the separation of closely related protein variants by differences in charge and molecular size. Smithies (1955) detected the amazing polymorphism of haptoglobin. In later years the method was extended to the study of allozymes (enzyme polymorphisms). 

Fig. 1. Overview of intravascular heme catabolism. Hemoglobin, myoglobin, and other heme proteins are released into the circulation upon cellular destruction, and the heme moiety is oxidized by O2 to the ferric form (e.g., methemoglobin and metmyoglobin). Haptoglobin can bind a substantial amount of hemoglobin, but is readily depleted. Ferric heme dissociates from globin and can be bound by albumin or more avidly by hemopexin. Hemopexin removes heme from the circulation by a receptor-mediated transport mechanism, and once inside the ceU heme is transported to heme oxygenase for catabolism.

Muscular activity effects the concentration of many biochemical constituents. Mild exercise, walking at a rate of 5.6 km/hour produced a 20% increase in creatine clearance (Kl). However, severe exercise (jogging at 10.5 km/hr) produced a 40% decrease in clearance (Kl). Mild exercise (a 3-hour march) produced a mean fall of 18.2 mg/100 ml in haptoglobin levels from pre-exercise concentrations of 84.5 mg/100 ml (H14). Similar observations have been made for thyroxine and hormonebinding proteins (D7). 

Determination of acute-phase proteins (CRP, orosomucoid, haptoglobin, transferrin, prealbumin), immunoglobulins (IgA, IgG, IgM), compressive markers (albumin, fibrinogen), markers of tissue destruction (Apo A-I, A-II, Apo B), components of complement (C3, C4), proteinase inhibitors (antithrombin HI, a -antitrypsin). The measurement was performed simultaneously in CSF and in serum (plasma) by a laser nephelometric method. The functional state of the blood-CSF barrier was evaluated numerically with the help of the quotient Q = Albcsp/s and also by the intrathecal synthesis of immunoglobulins according to Reiber s formula and for each class—IgG, IgM, IgA. 

It is often observed that the concentration of some other protein markers in cerebrospinal fluid is increased. In this respect, it is worth mentioning the increase in some acute-phase proteins, including transferrin, haptoglobin, and orosmucoid. Very frequently an increased concentration of the C3 component is observed in cerebrospinal fluid. Increased concentrations of apolipoproteins in cerebrospinal fluid are frequently seen as well, especially Apo A-I and, less distinctly, Apo B. Although these findings are common, they are also rather nonspecific, suggesting only that the destruction of tissue is present—in this case, the destruction of the central and peripheral myelin. 

Acute-phase proteins Above all orosomucoid and transferrin to a lesser extent, haptoglobin, prealbumin... 

These hormones also have profound effects on the function of the liver. Some of these effects are deleterious and will be considered below in the section on adverse effects. The effects on serum proteins result from the effects of the estrogens on the synthesis of the various 2 globulins and fibrinogen. Serum haptoglobins produced in the liver are depressed rather than increased by estrogen. Some of the effects on carbohydrate and lipid metabolism are probably influenced by changes in liver metabolism (see below). 

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