Transport Proteins are essential components within biological systems, acting as carriers for a wide array of molecules in the plasma. These proteins play multifaceted roles that extend beyond simple transportation. They are critical for solubilizing otherwise insoluble molecules, maintaining a balance of free and bound substances, and even neutralizing toxic compounds. Moreover, emerging research highlights their active involvement in cellular metabolism through interactions with receptors and enzymes.
| Protein | Mol. mass (Da) | Mean concentration (g/L) | Substance transported |
|---|---|---|---|
| Albumin | 68,000 | 40.0 | (see Table 28.14) |
| Transferrin | 77,000 | 2.8 | Iron |
| Ceruloplasmin | 130,000 | 0.35 | Copper |
| Haptoglobin | 100,000–400,000 | 2.0 | Hemoglobin |
| Hemopexin | 57,000 | 0.75 | Heme |
| Prealbumin | 55,000 | 0.3 | Vitamin A, Thyroxine |
| Retinol-binding protein | 21,000 | 0.045 | Vitamin A |
| Thyroxine-binding globulin | 57,000 | 0.035 | Thyroxine |
| Transcortin | 55,700 | 0.030 | Corticosteroids |
| Sex hormone-binding globulin | 94,000 | 0.020 | Androgens and Estrogens |
| Group component (Gc globulin) | 51,000 | 0.55 | Vitamin D |
| Transcobalamin I | 60,000–70,000 | 0.00003 | |
| II | 38,000 | 0.000015 | Vitamin B12 |
| III | 60,000–70,000 | 0.000025 | |
| Apolipoproteins | See Chapter 35 |
This table provides an overview of key transport proteins found in plasma, their molecular weights, typical concentrations, and the primary substances they transport, illustrating the diverse nature of these biological carriers.
Albumin: The Multifunctional Plasma Protein
Albumin, distinguished by its lack of carbohydrate residues unlike many other major plasma proteins and along with C-reactive protein, is a single-chain polypeptide. It features a unique thiol group, which can lead to albumin polymers forming in vitro by binding a half-cystine.
Functions of Albumin
Albumin is renowned for its capacity to bind a vast array of substances, particularly lipid-soluble anions. A significant portion of long-chain fatty acids in circulation is bound to albumin at hydrophobic sites, typically accommodating 1–2 fatty acid molecules per albumin molecule under normal conditions. These same binding sites are also used by bilirubin and various drugs, including salicylate, warfarin, phenylbutazone, and clofibrate. Competition for these sites can lead to clinically significant increases in drug activity, as only the unbound drug form is biologically active. Calcium also binds to albumin, albeit weakly, at approximately 16 sites.
Beyond substance transport, albumin is crucial in maintaining intravascular colloid osmotic pressure. This pressure differential between plasma and tissue fluid is vital for fluid distribution, although other proteins can partially compensate for albumin’s absence. Furthermore, cells can internalize albumin via pinocytosis and utilize it as an amino acid source.
Genetic Variations in Albumin
To date, 23 structural variants of albumin have been identified. These variants are inherited in an autosomal codominant manner, resulting in bisalbuminemia in heterozygotes, observable as two bands of equal staining intensity on electrophoresis. Some variants, however, can cause dimerization in vivo, leading to broadened or unevenly dense double albumin bands. Notably, these ‘para-albumins’ are not associated with any known diseases.
Analbuminemia, the near absence of albumin, is a rare condition. Typically, trace amounts of albumin are present, and affected individuals often exhibit minimal to no symptoms, or at most, mild edema.
Albumin Levels in Disease
Normal albumin levels are influenced by its distribution volume, synthesis rate, and catabolic rate. Disease states often involve changes in multiple factors affecting albumin levels, as detailed in Table 28.14. Hormonal fluctuations during the menstrual cycle and pregnancy can alter distribution volume, affecting albumin concentrations. Inflammation triggers an initial increase in distribution volume due to vascular permeability, followed by a cytokine-mediated reduction in albumin synthesis.
| Disease | Synthesis | Loss | Degradation rate | Exchangeable pool |
|---|---|---|---|---|
| Liver disease | ↓ | ↓ | ↑ | |
| Nephrotic syndrome | ↑ | ↑ | ↑ | ↓ |
| Protein-losing enteropathy | ↑ | ↑ | ↑ | ↓ |
| Malnutrition | ↓ | ↓ | ↓ | |
| Acute burn | ↑ ↓ | ↑ | ↑ | |
| Cushing’s syndrome | ↑ ↑ | ↑ | ↑ | |
| Thyrotoxicosis | ↑ ↑ | ↑ ↑ | ↑ |
Hypoalbuminemia, or low albumin levels, serves as a sensitive but non-specific indicator of illness. In many disease conditions, reduced albumin synthesis is attributable to malnutrition, while increased catabolism associated with injury and fever can shorten albumin’s half-life from a normal 21 days to as little as 7 days.
Liver disease frequently results in hypoalbuminemia, typically mild unless recovery is prolonged. In cirrhosis, hepatic albumin synthesis might be normal or even elevated, but much of the newly synthesized albumin leaks into hepatic lymph and ascitic fluid, diminishing its utility as a marker of liver function.
Increased glomerular permeability, as seen in nephrotic syndrome, leads to urinary albumin loss and edema when plasma albumin concentrations fall below 20 g/L. The degree of albuminuria, however, is not a reliable prognostic indicator, especially in children with minimal change nephritis, which can present with severe albuminuria.
Gastrointestinal protein loss is another significant cause of hypoalbuminemia, often stemming from inflammatory or neoplastic diseases. Fecal α1-antitrypsin measurement can quantify protein loss into the gut, as α1-antitrypsin resists degradation in the gut.
Diagram of serum albumin, a key transport protein, highlighting its polypeptide structure and crucial role in binding and transporting various molecules throughout the body.
Transferrin: The Iron Transporter
Transferrin, a 77 kDa protein, is the primary iron-transport protein in plasma. Synthesized predominantly in the liver and also in other tissues like the reticuloendothelial system, it features two iron-binding sites, likely with differing affinities, at its N-terminal and C-terminal ends. Transferrin is central to iron metabolism, recycling iron from hemoglobin and other protein catabolism back to hematopoietic tissues. Unlike some transport proteins, transferrin returns to circulation after releasing iron at cell membranes.
Pregnancy elevates transferrin concentrations, with levels in the last trimester exceeding those in other conditions. Oral contraceptive use also leads to increased levels. Iron deficiency stimulates hepatic synthesis, raising serum transferrin levels; the severity and duration of iron deficiency correlate with transferrin level increases.
Conversely, transferrin levels decrease in malnutrition, liver disease, and inflammatory conditions like rheumatoid arthritis, reflecting a negative acute-phase response that mirrors disease severity and chronicity.
Clinically, transferrin measurement, either immunochemically or as iron-binding capacity, is valuable in diagnosing anemia. Iron levels are typically assessed alongside transferrin, and protein saturation is calculated. Simple iron-deficiency anemia usually presents with elevated serum transferrin and low saturation, whereas anemia due to impaired iron incorporation into red cells shows normal or low transferrin with high saturation.
High transferrin saturation with normal transferrin levels is indicative of hemochromatosis and other iron overload conditions, useful for diagnosis and therapy monitoring, though serum ferritin measurement has largely superseded it.
Similar to other serum proteins, several rare allotypes of transferrin exist. Atransferrinemia, a rare condition marked by transferrin absence, results in iron-deficiency anemia unresponsive to iron therapy.
An artistic rendering of transferrin, a crucial transport protein, bound with ferric ions, illustrating its essential function in iron transport within the bloodstream.
Ceruloplasmin: The Copper-Carrying Protein
Ceruloplasmin, a distinctive sky-blue protein of 130 kDa, binds approximately 95% of plasma copper, with albumin carrying the remainder. Each ceruloplasmin molecule carries 8 copper atoms. Synthesized in the liver, its precise function remains debated.
Turnover studies using labeled copper suggest ceruloplasmin is not a primary physiological copper transport protein in vivo. Albumin likely transports copper from the gut to the liver. Copper attachment to ceruloplasmin occurs before secretion from liver cells, and increased hepatic copper pools enhance ceruloplasmin synthesis. Ceruloplasmin exhibits weak oxidase activity in plasma, potentially oxidizing ferrous ions to the ferric form for apotransferrin binding at the cell surface. In vitro, it shows antioxidant properties, inhibiting peroxidation by catalysts like iron, and may neutralize free radicals produced during phagocytosis, suggesting a role in inflammation, consistent with its acute-phase reactant behavior.
Most Wilson’s disease patients exhibit low plasma copper and ceruloplasmin concentrations. This genetic disorder results in copper deposition in tissues, particularly the liver (leading to cirrhosis) and brain (damaging basal ganglia), likely due to impaired biliary copper excretion and intracellular accumulation. A defective intracellular copper-binding protein might prevent copper from reaching biliary excretion pathways and ceruloplasmin binding pools, causing low plasma ceruloplasmin levels due to reduced intracellular copper availability.
Low plasma copper or ceruloplasmin levels are thus critical diagnostic indicators for Wilson’s disease, corroborated by liver biopsy demonstrating high copper levels.
Plasma ceruloplasmin concentrations decrease in severe liver disease, notably primary biliary cirrhosis and atresia, and in malabsorption. Conversely, pregnancy (last trimester) and estrogen-containing drugs elevate ceruloplasmin levels. As a slow acute-phase reactant, ceruloplasmin increases especially in reticuloendothelial system diseases like Hodgkin’s disease, serving as a disease activity marker. Infections and biliary tract obstructions also elevate ceruloplasmin, likely due to impaired biliary excretion, increasing hepatocellular copper pools and inducing ceruloplasmin synthesis.
A detailed molecular model of ceruloplasmin, a blue copper-binding transport protein, demonstrating its complex structure and role in copper homeostasis and redox reactions.
Other Notable Transport Proteins
Plasma lipids are transported as macromolecular micellar structures, solubilized by specific apolipoproteins. Hormone carrier proteins, listed in Table 28.13, are crucial for assessing free, biologically active hormone levels in plasma. The retinol-binding protein–prealbumin complex is notable for vitamin A transport.
Hemopexin (57 kDa) binds free heme released during intravascular hemolysis. The hemopexin–heme complex is then taken up by the liver, where iron is bound to ferritin and heme is converted to bilirubin by heme oxygenase. Hemolysis decreases serum hemopexin levels, which, unlike haptoglobin, is not an acute-phase reactant, so low levels persist even when haptoglobin levels normalize or rise due to inflammation.
In conclusion, transport proteins are indispensable for maintaining physiological balance and facilitating molecular trafficking within the body. Their diverse roles and specificities underscore their importance in health and disease.
