Magnesium biological role

Magnesium is an essential element in biological systems. Magnesium occurs typically as the Mg ion. [1][2][3] It is an essential mineral nutrient for life and is present in everycell type in every organism. For example, ATP (adenosine triphosphate), the main source of energy in cells, must be bound to a [4] magnesium ion in order to be biologically active. What is called ATP is often actually Mg-ATP. Similarly, magnesium plays a role in the stability of all polyphosphate compounds in the cells, including those associated withDNA- and RNA synthesis. Over 300 enzymes require the presence of magnesium ions for their catalytic action, including all enzymes utilizing or synthesizing ATP, or those that use other nucleotides to synthesize DNA and RNA. In plants, magnesium is necessary for synthesis of chlorophyll and photosynthesis.
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Function
A balance of magnesium is vital to the well being of all organisms. Magnesium is a relatively abundant ion in the lithosphere and is highly bioavailable in the hydrosphere. This availability, in combination with a useful and very unusual chemistry, may have led to its usefulness in evolution as an ion for signaling, enzyme activation and catalysis. However, the unusual nature of ionic magnesium has also led to a major challenge in the use of the ion in biological systems. Biological membranes are impermeable to magnesium (and other ions) so transport proteins must facilitate the flow of magnesium, both into and out of cells and intracellular compartments.

Biological range, distribution, and regulation

In animals it has been shown that different cell types maintain different concentrations of magnesium. It seems likely that the same is true for plants. This suggests that different cell types may regulate influx and efflux of magnesium in different ways based on their unique metabolic needs. Interstitial and systemic concentrations of free magnesium must be delicately maintained by the combined processes of buffering (binding of ions to proteins and other molecules) and muffling (the transport of ions to storage or extracellular spaces). In plants, and more recently in animals, magnesium has been recognized as an important signaling ion, both activating and mediating many biochemical reactions. The best example of this is perhaps the regulation of carbon fixation in chloroplasts in the Calvin cycle. The importance of magnesium to proper cellular function cannot be overstated. Deficiency of the nutrient results in disease in the affected organism. In single-celled organisms such as bacteria and yeast, low levels of magnesium manifests in greatly reduced growth rates. In magnesium transport knockout strains of bacteria, healthy rates are maintained only with exposure to very high [16] external concentrations of the ion. In yeast, mitochondrial magnesium deficiency also leads to disease. Plants deficient in magnesium show stress responses. The first observable signs of both magnesium starvation and overexposure in plants is a decrease in the rate ofphotosynthesis. This is due to the 2+ central position of the Mg ion in the chlorophyll molecule. The later effects of magnesium deficiency on plants are a significant reduction in growth and reproductive viability.Magnesium can also be toxic to plants, although this is typically seen only in drought conditions In animals, magnesium deficiency (hypomagnesemia) is seen when the environmental availability of magnesium is low. In ruminant animals, particularly vulnerable to magnesium availability in pasture grasses, the condition is known as grass tetany. Hypomagnesemia is identified by a loss of balance due to muscle weakness. A number of genetically attributable hypomagnesemia disorders have also been identified in humans.

Overexposure to magnesium may be toxic to individual cells, though these effects have been difficult to show experimentally. In humans the condition is termed hypermagnesemia, and is well documented, though it is usually caused by loss of kidney function. In healthy individuals, excess magnesium is rapidly excreted in the urine.

Human health
The adult human daily nutritional requirement, which is affected by various factors including gender, weight and size, is 300-400 mg/day. Inadequate magnesium intake frequently causes muscle spasms, and has been associated with cardiovascular disease, diabetes, high blood pressure, anxiety disorders, migraines, osteoporosis and cerebral infarction. Acute deficiency (see hypomagnesemia) is rare, and is more common as a drug side effect (such as chronic alcohol or diuretic use) than from low food intake per se, but it can also occur within people fed intravenously for extended periods of time. The incidence of chronic deficiency resulting in less than optimal health is debated. The DRI upper tolerated limit for supplemental magnesium is 350 mg/day (calculated as milligrams (mg) of elemental magnesium in the salt). (Supplements based on amino acid chelates, such as glycinate, lysinate etc., are much better tolerated by the digestive system and do not have the side effects of the older compounds used, while sustained release supplements prevent the occurrence of diarrhea.) The most common symptom of excess oral magnesium intake is diarrhea. Since the kidneys of adult humans excrete excess magnesium efficiently, oral magnesium poisoning in adults with normal renal function is very rare. Infants, which have less ability to excrete excess magnesium even when healthy, should not be given magnesium supplements, except under a physician's care. Pharmaceutical preparations with magnesium are used to treat conditions including magnesium [26] deficiency and hypomagnesemia, as well as eclampsia. Such preparations are usually in the form of magnesium sulfate or chloride when given parenterally. Magnesium is absorbed with reasonable efficiency (30% to 40%) by the body from any soluble magnesium salt, such as the chloride or citrate. Magnesium is similarly absorbed from Epsom salts, although the sulfate in these salts adds to their laxative effect at higher doses. Magnesium absorption from the insoluble oxide and hydroxide salts (milk of magnesia) is erratic and of poorer efficiency, since it depends on the neutralization and solution of the salt by the acid of the stomach, which may not be (and usually is not) complete. Magnesium orotate may be used as adjuvant therapy in patients on optimal treatment for severe congestive heart failure, increasing survival rate and improving clinical symptoms and patient's ] quality of life.

Nerve conduction
Magnesium can affect muscle relaxation through direct action on cell membranes. Mg ions close certain types of calcium channels, which conduct a positively charged calcium ion into neurons. With an excess of magnesium, more channels will be blocked and nerve cells will have less activity.
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Hypertension
Magnesium-containing Epsom salts are especially used in treating the hypertension of eclampsia. Even if the case is not eclampsia, there may be antihypertensive effects of having a substantial portion of the intake of sodium chloride (NaCl) exchanged for e.g. magnesium chloride; NaCl is an osmolite and increases arginine vasopressin (AVP) release, which increases extracellular volume and thus results in increased blood pressure. However, not all osmolites have this effect on AVP release, so with magnesium chloride, the increase in osmolarity may not cause such a hypertensive response.

Food sources
Green vegetables such as spinach provide magnesium because of the abundance of chlorophyll molecules which contain the ion. Nuts (especially cashews and almonds), seeds, dark ] chocolate, roasted soybeans, bran, and some whole grains are also good sources of magnesium.

Although many foods contain magnesium, it is usually found in low levels. As with most nutrients, daily needs for magnesium are unlikely to be met by one serving of any single food. Eating a wide variety of fruits, vegetables, and grains will help ensure adequate intake of magnesium. Because magnesium readily dissolves in water, refined foods, which are often processed or cooked in water and dried, are generally poor sources of the nutrient. For example, whole wheat bread has twice as much magnesium as white bread because the magnesium-rich germ and bran are removed when white flour is processed. The table of food sources of magnesium suggests many dietary sources of magnesium. "Hard" water can also provide magnesium, but "soft" water does not contain the ion. Dietary surveys do not assess magnesium intake from water, which may lead to underestimating total magnesium intake and its variability. Too much magnesium may make it difficult for the body to absorb calcium. Not enough magnesium can lead to hypomagnesemiaas described above, with irregular heartbeats, high blood pressure (a sign in humans but not some experimental animals such as rodents), insomnia and muscle spasms (fasciculation)However, as noted, symptoms of low magnesium from pure dietary deficiency are thought to be rarely encountered. Following are some foods and the amount of magnesium in them Black-eyed peas (1/2 cup) = 45 mg Buckwheat flour (100g (4 oz)) = 250 mg Halibut (100g (4 oz)) = 107 mg Milk: low fat (1 cup) = 40 mg Oats (100g (4 oz)) = 235 mg Peanut butter (2 tablespoons) = 50 mg Spinach (1/2 cup) = 80 mg Wholemeal bread (1 Slice) = 25 mg

Biological chemistry
Mg is the fourth most abundant metal ion in cells (in moles) and the most abundant free divalent cation 2+ as a result it is deeply and intrinsically woven into cellular metabolism. Indeed, Mg -dependent 2+ enzymes appear in virtually every metabolic pathway: specific binding of Mg to biological membranes is 2+ frequently observed, Mg is also used as a signalling molecule, and much of nucleic acid biochemistry 2+ requires Mg , including all reactions which require release of energy from ATP. In nucleotides, the triple 2+ phosphate moiety of the compound is invariably stabilized by association with Mg in all enzymic processes.
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Chlorophyll
In photosynthetic organisms Mg has the additional vital role of being the coordinating ion in the chlorophyll molecule. This role was discovered by R. M. Willsttter, who received the Nobel Prize in Chemistry 1915 for the purification and structure of chlorophyll.
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Enzymes
The chemistry of the Mg ion, as applied to enzymes, uses the full range of this ions unusual reaction [30][32][33][34] 2+ chemistry to fulfill a range of functions. Mg interacts with substrates, enzymes and 2+ 2+ occasionally both (Mg may form part of the active site). Mg generally interacts with substrates through inner sphere coordination, stabilising anions or reactive intermediates, also including binding to ATP and activating the molecule to nucleophilic attack. When interacting with enzymes and other proteins 2+ Mg may bind using inner or outer sphere coordination, to either alter the conformation of the enzyme or 2+ take part in the chemistry of the catalytic reaction. In either case, because Mg is only rarely fully 2+ dehydrated during ligand binding, it may be a water molecule associated with the Mg that is important
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rather than the ion itself. The Lewis acidity of Mg (pKa 11.4) is used to allow both hydrolysis and condensation reactions (most commonly phosphate ester hydrolysis and phosphoryl transfer) that would otherwise require pH values greatly removed from physiological values.

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Essential role in the biological activity of ATP

ATP (adenosine triphosphate), the main source of energy in cells, must be bound to a magnesium ion in [4] order to be biologically active. What is called ATP is often actually Mg-ATP. [edit]Nucleic acids Nucleic acids have an important range of interactions with Mg . The binding of 2+ Mg to DNA and RNA stabilises structure; this can be observed in the increased melting temperature 2+ (Tm) of double-stranded DNA in the presence of Mg . Additionally, ribosomes contain large amounts of 2+ Mg and the stabilisation provided is essential to the complexation of this ribo-protein. A large number of 2+ enzymes involved in the biochemistry of nucleic acids bind Mg for activity, using the ion for both activation and catalysis. Finally, the autocatalysis of many ribozymes (enzymes containing only RNA) is 2+ [ Mg dependent (e.g. the yeast mitochondrial group II self splicing introns ). Magnesium ions can be critical in maintaining the positional integrity of closely clustered phosphate groups. These clusters appear in numerous and distinct parts of the cell nucleus and cytoplasm. For 2+ instance hexahydrated Mg ions bind in the deep major groove and at the outer mouth of A-form nucleic acid duplexes.
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Cell membranes and walls

Biological cell membranes and cell walls are polyanionic surfaces. This has important implications for the transport of ions, particularly because it has been shown that different membranes preferentially bind [30] 2+ 2+ different ions. Both Mg and Ca regularly stabilise membranes by the cross-linking of carboxylated and phosphorylated head groups of lipids. However, the envelope membrane of E. coli has also been + + 2+ 3+ shown to bind Na , K , Mn and Fe . The transport of ions is dependent on both the concentration gradient of the ion and the electric potential () across the membrane, which will be affected by the 2+ charge on the membrane surface. For example, the specific binding of Mg to the chloroplastenvelope + has been implicated in a loss of photosynthetic efficiency by the blockage of K uptake and the subsequent acidification of the chloroplast stroma.

Proteins
The Mg ion tends to bind only weakly to proteins (Ka 10 ) and this can be exploited by the cell to 2+ switch enzymatic activity on and off by changes in the local concentration of Mg . Although the 2+ 2+ concentration of free cytoplasmic Mg is on the order of 1 mmol/L, the total Mg content of animal cells [38] is 30 mmol/L and in plants the content of leaf endodermal cells has been measured at values as high as 100 mmol/L (Stelzer et al., 1990), much of which is buffered in storage compartments. The cytoplasmic 2+ concentration of free Mg is buffered by binding to chelators (e.g. ATP), but also more importantly by 2+ 2+ storage of Mg in intracellular compartments. The transport of Mg between intracellular compartments 2+ may be a major part of regulating enzyme activity. The interaction of Mg with proteins must also be considered for the transport of the ion across biological membranes.
2+ 5[30]

Manganese
In biological systems, only manganese (Mn ) is readily capable of replacing Mg , but only in a limited set 2+ 2+ of circumstances. Mn is very similar to Mg in terms of its chemical properties, including inner and outer 2+ shell complexation. Mn effectively binds ATP and allows hydrolysis of the energy molecule by most 2+ 2+ 2+ ATPases. Mn can also replace Mg as the activating ion for a number of Mg -dependent enzymes, [30] although some enzyme activity is usually lost. Sometimes such enzyme metal preferences vary among closely related species: for example, the reverse transcriptase enzyme 2+ of lentiviruses like HIV, SIV and FIV is typically dependent on Mg , whereas the analogous enzyme for 2+ otherretroviruses prefers Mn .
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Importance in drug binding

An article investigating the structural basis of interactions between clinically relevant antibiotics and the 50S ribosome appeared in Nature in October 2001. High resolution x-ray crystallography established that these antibiotics only associate with the 23S rRNA of a ribosomal subunit, and no interactions are formed with a subunit's protein portion. The article stresses that the results show "the importance of putative 2+ Mg ions for the binding of some drugs".
[39]