Glucosamine sulfate (GS) is a monosaccharide (simple sugar) and belongs to the carbohydrates. It is a derivative (descendant) of D-glucose (dextrose), from which GS differs only in the substitution (replacement) of the hydroxy (OH) group on the second carbon (C) atom by an amino (NH2) group – amino sugar, D-glucosamine – and in the presence of a sulfate (SO4) group – D-glucosamine sulfate – attached to the NH2 group. Glucosamine – mostly in the form of N-acetylglucosamine (GlcNAc) or glucosamine sulfate – is the basic molecule of glycosaminoglycans, those mucopolysaccharides consisting of repetitive (repeating) disaccharide (two-sugar) units (uronic acid + amino sugar) and the carbohydrate side chains of high-molecular-weight proteoglycans (glycosylated glycoproteins, which are important components of the extracellular matrix (extracellular matrix, intercellular substance, ECM, ECM), especially of bone, cartilage and tendons). Depending on the composition of the disaccharide units, different glycosaminoglycans can be distinguished from each other – hyaluronic acid (glucuronic acid + N-acetylglucosamine), chondroitin sulfate and dermatan sulfate (glucuronic acid or iduronic acid + N-acetylgalactosamine), Heparin and heparan sulfate (glucuronic acid or iduronic acid + N-acetylglucosamine or glucosamine sulfate), and keratan sulfate (galacturonic acid + N-acetylglucosamine). All glycosaminoglycans have in common that they possess negative charges and thus attract sodium ions (Na2+), which in turn induce water influx. For this reason, glycosaminoglycans are able to bind water, which plays an essential role, especially for the functionality of articular cartilage. With age, the charge density of glycosaminoglycans decreases and their water-binding capacity decreases, causing cartilage tissue to lose hardness and elasticity and structural changes to occur. Finally, the risk of arthritic disease increases with age.
Synthesis
Glucosamine is synthesized (formed) in the human organism from D-fructose-6-phosphate and the amino acid L-glutamine. While the fructose molecule as hexose (C6 body) provides the basic molecular skeleton, glutamine provides the amino group. The biosynthesis of glucosamine begins with the transfer of the NH2 group of glutamine to the C5 body of fructose-6-phosphate by glutamine-fructose-6-phosphate transaminase, so that glucosamine-6-phosphate is formed after subsequent isomerization. This is followed by dephosphorylation (cleavage of the phosphate group) to glucosamine and binding of a hydrochloride (HCl) group to its amino group – glucosamine hydrochloride – which is replaced by a sulfate group – glucosamine sulfate – in the next step. In the context of therapeutic application, glucosamine and glucosamine hydrochloride and glucosamine sulfate, respectively, are produced industrially. The starting material is chitin (Greek chiton “undercoat, shell, carapace”) – a nitrogen (N)-containing polysaccharide widely distributed in nature, especially in the animal and fungal kingdoms, which is the main component of the exoskeleton of many arthropods (arthropods), a component of the radula (mouthparts) of many mollusca (mollusks) and a cell wall component of some fungi. The framework substance chitin is composed of several monomers (up to 2,000), predominantly N-acetyl-D-glucosamine (GlcNAc), but may also contain D-glucosamine units. The monomers are linked to each other by ß-1,4-glycosidic bonds. For industrial glucosamine synthesis, chitin is mainly obtained as a secondary raw material from fishery wastes of crustaceans, such as crabs and shrimps. For this purpose, crushed crayfish shells and crab shells are deproteinized by means of sodium hydroxide solution (2 mol NaOH/l) and freed from lime components under the action of hydrochloric acid (4 mol HCl/l). The resulting polymer chitin is treated with hot hydrochloric acid to hydrolytically cleave it (by reaction with water) into its monomers and to deacetylate them (cleavage of the acetyl group from GlcNAc; if the degree of acetylation is < 50 %, it is referred to as chitosan), giving rise to numerous D-glucosamine molecules. Bonding of HCl or SO4 groups to the amino groups of the glucosamine molecules results in D-glucosamine hydrochlorides or D-glucosamine sulfates, respectively. Glucosamine is the preferred substrate for the biosynthesis of glycosaminoglycans.Following the amidation and isomerization of fructose-6-phosphate to glucosamine-6-phosphate, the latter is acetylated to N-acetylglucosamine-6-phosphate by glucosamine-6-phosphate N-acetyltransferase, is isomerized (converted) to N-acetylglucosamine-1-phosphate by N-acetylglucosamine phosphoglucomutase and converted to UDP-N-acetylglucosamine (UDP-GlcNAc) by uridine diphosphate (UDP)-N-acetylglucosamine phosphorylase, which in turn can be converted to UDP-N-acetylgalactosamine (UDP-GalNAc) by UDP-galactose 4-epimerase. The nucleotide UDP provides the necessary energy to transfer the GlcNAc or GalNAc molecule to a uronic acid and thus synthesize the disaccharide units of glycosaminoglycans, such as hyaluronic acid, chondroitin sulfate/dermatan sulfate and keratan sulfate. To biosynthesize heparin and heparan sulfate, the GlcNAc residue is partially deacetylated and sulfated to glucosamine sulfate. With age, the ability to self-produce glucosamine in sufficient amounts decreases, which is associated with decreased glycosaminoglycan synthesis. For this reason, aging articular cartilage is subject to structural changes and increasingly loses its function as a shock absorber. Consequently, the elderly are at increased risk of developing osteoarthritis and other arthritic changes.
Resorption
Very little is known to date about the mechanism of intestinal (involving the intestines) absorption (uptake) of glucosamine and glucosamine sulfate. There is evidence that glucosamine enters enterocytes (cells of the small intestinal epithelium) in the upper small intestine by an active process involving transmembrane transport proteins (carriers). An essential role seems to be played by the sodium/glucose cotransporter-1 (SGLT-1), which transports D-glucose and D-glucose derivatives, including D-glucosamine, together with sodium ions by means of a symport (rectified transport) from the duodenum to the ileum. For the absorption of glucosamine sulfate, an enzymatic cleavage of the sulfate group is necessary in the intestinal lumen or at the brush border membrane of the enterocytes in order to be internalized (taken up internally) by the SGLT-1 in the form of glucosamine. The SGLT-1 is expressed in dependence on the luminal substrate concentration – when substrate supply is high, intracellular expression of the carrier system and its incorporation into the apical (facing the intestinal lumen) enterocyte membrane is increased, and when substrate supply is low, it is decreased. In this process, substrates compete for SGLT-1 binding sites so that, for example, glucosamine is displaced from the site of absorption at high luminal glucose concentrations. The driving force of SGLT-1 is an electrochemical, inward cellular sodium gradient, which is mediated by the sodium (Na+)/potassium (K+)-ATPase, located in the basolateral (facing the blood vessels) cell membrane, and is activated by consumption of ATP (adenosine triphosphate, universal energy-providing nucleotide) catalyzes (accelerates) the transport of Na+ ions from the intestinal cell into the bloodstream and K+ ions into the intestinal cell. In addition to the apical enterocyte membrane, SGLT-1 is also located in the proximal tubule of the kidney (main part of the renal tubules), where it is responsible for the reabsorption of glucose and glucosamine. In enterocytes (cells of the small intestinal epithelium), enzymatic resulfation (attachment of sulfate groups) of glucosamine to glucosamine sulfate occurs, although this may also occur in liver and other organs. The transport of glucosamine and glucosamine sulfate from enterocytes through the basolateral cell membrane into the bloodstream (portal vein) is accomplished by glucose transporter-2 (GLUT-2). This carrier system has a high transport capacity and low substrate affinity, so that in addition to glucose and glucose derivatives, galactose and fructose are also transported. GLUT-2 is also localized in liver and pancreatic beta cells (insulin-producing cells of the pancreas), where it ensures both carbohydrate uptake into the cells and release into the bloodstream. According to pharmacokinetic studies, intestinal absorption of orally supplied glucosamine and glucosamine sulfate is rapid and almost complete (up to 98%).The high availability of glucosamine sulfate results in part from its small molar mass or molecular size compared to glycosaminoglycans – the GS molecule is about 250 times smaller than the chondroitin sulfate molecule. The absorption rate of chondroitin sulfate is estimated to be only 0-8%.
Transport and distribution in the body
Studies with radiolabeled, orally administered glucosamine and glucosamine sulfate showed that these substances appear rapidly in the blood after rapid absorption and are rapidly taken up by tissues and organs. The amino sugars are incorporated preferentially into joint structures, especially into the extracellular (outside the cell) matrix (extracellular matrix, intercellular substance, ECM, ECM) of cartilage, ligaments and tendons. There, glucosamine sulfate is the predominant form because free glucosamine undergoes enzymatic sulfation (attachment of sulfate groups). In the joint, glucosamine sulfate stimulates the synthesis of cartilage components and synovial fluid (joint fluid). In addition, GS leads to increased absorption of sulfur, an essential element for joint tissues, where it is responsible for stabilizing the extracellular matrix of joint structures. By promoting anabolic (building up) processes and inhibiting catabolic (breaking down) processes in articular cartilage, glucosamine sulfate regulates the dynamic balance of cartilage building up and breaking down. Finally, GS is essential for maintaining joint function and is used as a dietary supplement or chondroprotectant (substances that protect cartilage and inhibit cartilage degradation with anti-inflammatory effects) in arthritic diseases. In doses of 700-1,500 mg per day, GS exhibits symptom-modifying activity with good tolerability and counteracts the progression of osteoarthritis. For example, treatment with 1,500 mg of orally administered GS reduced the 0.31-mm narrowing of the knee joint space expected in patients with gonarthrosis (knee joint osteoarthritis) by 70% within three years. GS uptake into articular cartilage follows an active mechanism via transmembrane carriers – as does the transport of glucosamine sulfate into the liver and kidney. Most other tissues take up the amino sugar by passive diffusion. In blood plasma, the residence time of glucosamine and glucosamine sulfate is very short – on the one hand, due to rapid uptake into tissues and organs, and on the other hand, due to incorporation (uptake) into plasma proteins, such as alpha- and beta-globulin. According to pharmacokinetic studies, orally administered glucosamine has a plasma concentration 5 times lower than parenterally (intravenously or intramuscularly) administered glucosamine. This is due to first-pass metabolism in the liver, which only oral glucosamine undergoes. As part of the first-pass effect, a high proportion of glucosamine is degraded to smaller molecules and ultimately to carbon dioxide, water, and urea, leaving only a small proportion of glucosamine unchanged and released into the bloodstream.
Excretion
Glucosamine sulfate is excreted predominantly through the kidneys in the urine (~30%), primarily in the form of glucosamine. Because of almost complete intestinal absorption, excretion of GS in feces (stool) is only about 1%. To a lesser extent, GS elimination also occurs in the respiratory tract.
