Magnesium in biology

Magnesium is an essential element in biological systems. Magnesium occurs typically as the Mg2+ ion. It is an essential mineral nutrient (i.e., element) for life and is present in every cell type in every organism. For example, ATP (adenosine triphosphate), the main source of energy in cells, must be bound to a magnesium ion in order to be biologically active. What is called ATP is often actually Mg-ATP. As such, magnesium plays a role in the stability of all polyphosphate compounds in the cells, including those associated with the synthesis of DNA and RNA.

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.

Function

A balance of magnesium is vital to the well-being of all organisms. Magnesium is a relatively abundant ion in Earth's crust and mantle and is highly bioavailable in the hydrosphere. This availability, in combination with a useful and very unusual chemistry, may have led to its utilization 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.

Chlorophyll in plants converts water to oxygen as O2. Hemoglobin in vertebrate animals transports oxygen as O2 in the blood. Chlorophyll is very similar to hemoglobin, except magnesium is at the center of the chlorophyll molecule and iron is at the center of the hemoglobin molecule, with other variations. This process keeps living cells on earth alive and produces levels of CO2 and O2 in our atmosphere that has changed with industrialization.

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.

Magnesium is very important in cellular function. Deficiency of the nutrient causes disease of the affected organism. In single-cell 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 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 of photosynthesis. This is due to the central position of the Mg2+ 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.[citation needed] Hypermagnesemia, an overabundance of magnesium in the blood, is usually caused by loss of kidney function. Healthy animals rapidly excrete excess magnesium in the urine and stool. Urinary magnesium is called magnesuria.

Human health

Further information: Magnesium deficiency (medicine)

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 DRI upper tolerated limit for supplemental magnesium is 350 mg/day, calculated as milligrams (mg) of elemental magnesium in the salt. The most common symptom of excess oral magnesium intake is diarrhea. 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 dietary supplements prevent the occurrence of diarrhea.[citation needed] 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 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. Mg2+ 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.

Hypertension

Intravenous magnesium is used in treating pre-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.[clarification needed]

Glucose tolerance

Magnesium deficiency is associated with insulin resistance, and chronic magnesium supplementation may improve insulin sensitivity.

Dreaming

Some supplemental magnesium users report an increase in vivid dreaming.

Food sources

Green vegetables such as spinach provide magnesium because of the abundance of chlorophyll molecules, which contain the ion. Nuts (especially brazil nuts, cashews and almonds), seeds (e.g., pumpkin 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, in general, are 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 contains less of 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.[citation needed] Not enough magnesium can lead to hypomagnesemia as 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

Mg2+ is the fourth-most-abundant metal ion in cells (per moles) and the most abundant free divalent cation — as a result, it is deeply and intrinsically woven into cellular metabolism. Indeed, Mg2+-dependent enzymes appear in virtually every metabolic pathway: Specific binding of Mg2+ to biological membranes is frequently observed, Mg2+ is also used as a signalling molecule, and much of nucleic acid biochemistry requires Mg2+, including all reactions that require release of energy from ATP. In nucleotides, the triple-phosphate moiety of the compound is invariably stabilized by association with Mg2+ in all enzymic processes.

Chlorophyll

In photosynthetic organisms, Mg2+ has the additional vital role of being the coordinating ion in the chlorophyll molecule. This role was discovered by Richard Willstätter, who received the Nobel Prize in Chemistry 1915 for the purification and structure of chlorophyll.

Enzymes

The chemistry of the Mg2+ ion, as applied to enzymes, uses the full range of this ion’s unusual reaction chemistry to fulfill a range of functions. Mg2+ interacts with substrates, enzymes, and occasionally both (Mg2+ may form part of the active site). In general, Mg2+ 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, Mg2+ may bind using inner or outer sphere coordination, to either alter the conformation of the enzyme or take part in the chemistry of the catalytic reaction. In either case, because Mg2+ is only rarely fully dehydrated during ligand binding, it may be a water molecule associated with the Mg2+ that is important rather than the ion itself. The Lewis acidity of Mg2+ (pKa 11.4) is used to allow both hydrolysis and condensation reactions (most common ones being phosphate ester hydrolysis and phosphoryl transfer) that would otherwise require pH values greatly removed from physiological values.

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 order to be biologically active. What is called ATP is often actually Mg-ATP.

Nucleic acids

Nucleic acids have an important range of interactions with Mg2+. The binding of Mg2+ to DNA and RNA stabilises structure; this can be observed in the increased melting temperature (Tm) of double-stranded DNA in the presence of Mg2+. In addition, ribosomes contain large amounts of Mg2+ and the stabilisation provided is essential to the complexation of this ribo-protein. A large number of enzymes involved in the biochemistry of nucleic acids bind Mg2+ for activity, using the ion for both activation and catalysis. Finally, the autocatalysis of many ribozymes (enzymes containing only RNA) is Mg2+ 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 instance, hexahydrated Mg2+ ions bind in the deep major groove and at the outer mouth of A-form nucleic acid duplexes.

Cell membranes and walls

Biological cell membranes and cell walls are polyanionic surfaces. This has important implications for the transport of ions, in particular because it has been shown that different membranes preferentially bind different ions. Both Mg2+ and Ca2+ regularly stabilize membranes by the cross-linking of carboxylated and phosphorylated head groups of lipids. However, the envelope membrane of E. coli has also been shown to bind Na+, K+, Mn2+ and Fe3+. The transport of ions is dependent on both the concentration gradient of the ion and the electric potential (ΔΨ) across the membrane, which will be affected by the charge on the membrane surface. For example, the specific binding of Mg2+ to the chloroplast envelope 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 Mg2+ ion tends to bind only weakly to proteins (Ka ≤ 105) and this can be exploited by the cell to switch enzymatic activity on and off by changes in the local concentration of Mg2+. Although the concentration of free cytoplasmic Mg2+ is on the order of 1 mmol/L, the total Mg2+ content of animal cells 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 buffered in storage compartments. The cytoplasmic concentration of free Mg2+ is buffered by binding to chelators (e.g., ATP), but also, what is more important, by storage of Mg2+ in intracellular compartments. The transport of Mg2+ between intracellular compartments may be a major part of regulating enzyme activity. The interaction of Mg2+ with proteins must also be considered for the transport of the ion across biological membranes.

Manganese

In biological systems, only manganese (Mn2+) is readily capable of replacing Mg2+, but only in a limited set of circumstances. Mn2+ is very similar to Mg2+ in terms of its chemical properties, including inner and outer shell complexation. Mn2+ effectively binds ATP and allows hydrolysis of the energy molecule by most ATPases. Mn2+ can also replace Mg2+ as the activating ion for a number of Mg2+-dependent enzymes, although some enzyme activity is usually lost. Sometimes such enzyme metal preferences vary among closely related species: For example, the reverse transcriptase enzyme of lentiviruses like HIV, SIV and FIV is typically dependent on Mg2+, whereas the analogous enzyme for other retroviruses prefers Mn2+.

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 associate only 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 Mg2+ ions for the binding of some drugs".