Chapter 6. Magnesium
As the eleventh most abundant mineral in the body, magnesium is one of the more
ubiquitous minerals, occurring in every cell and organ, but like calcium it has its largest deposit
in bone and muscle. Its multitude of functions comprise a wide range of biological processes,
most of which center on its use as an enzyme cofactor targeted to substrates containing
phosphate groups.
History and Early Insights
The word magnesium comes from the Greek Magnesia, referring to a district in the area
of Thessaly in the southeastern part of central Greece. This same region is credited with the
discovery of magnetite and manganese. Magnesium’s importance in biology drew attention
when the sulfate salt of magnesium was shown to be the active factor in Epson salts, which at
the time had been noted for healing properties. A greater insight into biological significance,
however, came when magnesium was shown to be one of the more abundant mineral in sea
waters, the caldron of life.
Chemical Properties
Magnesium is an alkaline earth metal sitting just above calcium in the periodic table of
elements. It has an atomic number is 12 and atomic weight of 24. Like calcium, its most stable
oxidation state is +2 which draws attention to a possible overlap in properties of Mg2+ and
Ca2+. Being only two-thirds the size of calcium, however, magnesium ions are distinct from
calcium in certain properties, most notably the binding strength to proteins and other
biological ligands. Mg2+ behaves mainly as a spherical ion with little tendency to share electron
or enter into coordinate covalent bonding. The absence of 3d electrons makes complexes of
Mg2+ colorless.
Solubility considerations
The salts of magnesium for the most part are readily soluble in water. This property
allows Mg2+ to exist as a freely diffusible cation inside cells. A mark of Mg2+ solubility is noted
by its concentration in sea water (50 mM); fresh water has a magnesium concentration of less
than 0.1 mM. The cytosolic concentration of magnesium approaches 1 mM, a concentration
that attests to its prevalence inside cells, but because its high concentration within also
explains why Mg2+ is unable to form a gradient across the cell membrane.
Biochemical Properties
Most of the attention on magnesium focuses on its role as a cofactor for kinase
enzymes, a family of enzymes that use ATP as a source of phosphate in energy-transfer
reactions in cells. A familiar example is hexokinase, the enzyme that transfers a phosphate
group from ATP to glucose or other monosaccharides as a first step in the glycolysis pathway.
A subclass of kinases, the protein kinases, target proteins as receivers of phosphate groups.
The protein kinases are particularly noteworthy since these enzymes are subject to regulation
by cell signaling agents and hormones. Their action is testament to varied roles of magnesium
at the biochemical level of cell function.
Because of a strongly intense 2+ charge, magnesium ions would be predicted to engage
primarily in electronstatic bonding with negative ions where charge is a primary determinant of
bonding strength. There are very few instances in biology can engage in covalent bonding.
The most notable example is covalently-bound magnesium in the ring structure of chlorophyll.
Selection of Mg2+ for this role is uncertain, but its smaller size and lack of redox properties fit
with its role in the light-capture property of chlorophyll. Other biochemical processes that rely
on magnesium are the synthesis of cholesterol, where Mg2+ ions not only assist in forming the
pyrophosphate bond from Mg-ATP in cholesterol precursors, but also in subsequent
condensations reaction that give rise to the familiar ring structure of cholesterol. Magnesium is
also a prominent in the nucleus and cytosol where it serves as a crosslinking ion that stabilizes
DNA and RNA. It is also instrumental to the stability and overall architecture of the cell
membrane, a property it shares with calcium and to a lesser extent zinc. Stabilization is
brought about by acting as a bridging ion between phosphorylated and carboxylated
molecules.
Enzyme Cofactors
Table X.1. Non-structural roles of calcium in biology
Passive Functions
Enzyme cofactor (lipases, hydrolases)
Blood clotting cascade
Active Functions
Relaxation and constriction of blood vessels
Cell aggregation
Muscle protein contraction
Cellular protein turnover
Hormone secretion
Nervous impulse transmission
Intracellular trafficking
Cell signaling
Genetic expression
Apoptosis
Table x.4. Enzymes dependent on calcium for function
Enzyme
Location
Function
Phospholipase A2
Lipase
Thermolysin
Trypsin
intestine
intestine
bacteria
duodenum
acylphospholipid hydrolysis
triacylglycerol hydrolysis
protein hydrolysis
protein digestion
Nutritional Properties
In 1997 the Food and Nutrition Board of the institute of Medicine revised the
magnesium requirement upward to the values shown in Table 6.x. The need for changes was
based on balance studies that utilized more sensitive methods for measuring magnesium.
Based on balance studies an adult human requires between 450-500 mg of magnesium per day
to stay in magnesium balance. The balance approach, however, cannot be applied to children
under the ages of six whose only source of magnesium is mother’s milk or formula.
Consequently there is insufficient information to establish an RDA for infants. After 6 months
and up to three years it is possible to discern an RDA of under 100 mg/day for infants and
toddlers (Table 6.x). Gender differences are not seen until early adulthood. Pregnancy and
lactation bring about only a modest increase in the RDA for magnesium. By comparison, the
requirement for magnesium at its highest level is still less than one half the calcium
requirement for individuals of the same age and gender. The intake of magnesium tends to
wane as a person grows older.
Table 6.x. Magnesium Requirement
RDA
Life Stage
Age
Males
Females
(mg/day)
(mg/day)
____________________________________________________
Children
1-3 years
80
80
Children
4-8 years
130
130
Children
9-13 years
240
240
Adolescent
14-18 years
410
380
Adult
19-30 years
400
310
Adult
31-50 years
420
320
Adult
>51 years
420
350
Pregnant
19-30 years
350
Pregnant
31-50 years
360
Lactating
19-30 years
310
Lactating
31-50 years
320
Food Sources
A summary of food sources for magnesium is shown in Table 6.x. Green leafy
vegetables, legumes, whole grains, nuts and shell fish are the richest source, estimated to be
around 500 mg per kilogram of fresh weight. Meats, starches and milk tend to be
intermediate, generally amounting to less than 30 percent of the dietary intake of magnesium
per day. Refined foods tend to have the lowest magnesium content. Hard water is particularly
rich in magnesium and is a good source (as opposed to soft water) for that reason. The rise in
refined foods entering the food chain gives justice to the statement that presently only about
one-third of Americans meet the daily requirement for magnesium.
Table x.2. Food Sources of Magnesium
Richest: (500 milligrams/1000 grams)
Green leafy vegetables
Wheat-soy flower
Shell fish
Middle
Milk
Banana
Lowest
White flour (refined)
Diet and Bioavailability
Absorption efficiency for magnesium is very high, ranging from near 50-90 percent from
human milk and formula to around 50 percent for solid food. The high solubility of magnesium
in water and the failure to form strong complexes with proteins and other macromolecules in
the food source is perhaps one reason. Two notable exceptions are foods high in fiber that
contain phytic acid. This combined with diets rich in phosphate are a major deterrent to
magnesium absorption. As noted previously, phosphate salts and organic phosphate
compounds have a strong attraction for divalent cations such as Ca2+ and Zn2+. Magnesium
(Mg2+) does not escape this attraction.
Dietary Supplements
A typical adult supplement for magnesium is around 100 mg/day with women tending to
take more than men. For children, the number is around 25 mg/day. Most of the supplement is
MgO, which accounts for nearly 60 percent by weight. The order of occurrence in supplements
is MgO> MgCO3> Mg(OH)2 > Mg-citrate >Mg-lactate >MgCl2>MgSO4.
Upper Limit
Based on milk alkali syndrome which is a measure of renal insufficiency, there is no
upper limit for magnesium in food and water. For magnesium in the form of supplements or
fortified foods, the upper limit for children 1-3 years is 65 mg/day; for 4-8, 100 mg/day and for
adults 350 mg/day.
Digestion and Absorption
Digestion
With the exception of a chlorophyll-magnesium complex in green leafy vegetables,
magnesium in foods is generally present as a weak complex with other food molecules. This
allows the magnesium to readily dissociate and enter the system as a soluble cation. As with
calcium, salivary amylases combined with mastication assist in the release of magnesium ions
from glycogen and starch, although a greater portion is liberated by amylases in the proximal
intestine. Proteases in the stomach and duodenum also liberate magnesium as does the highly
acidic gastric juice environment of the stomach.
Absorption
On first impression one may consider the absorption of magnesium to mimic calcium.
Such is not the case, however. Like calcium, magnesium is absorbed all along the intestinal
tract with the ileum and colon, not the jejunum, being more active. Like calcium, magnesium
employs both active (energy-dependent) mediated and passive (diffusion-driven) paracellular
transport. Active is characterized by saturation with increased intake. Generally the response
is curvilinear, suggesting saturation at the higher levels of intake and diffusion at the lower.
Diffusion, however, only accounts for 7-10% of the magnesium taken in. This signals
involvement of mediating factors that oversee the movement across the membrane and
through the cell. Unique to magnesium that was not seen with either sodium or potassium is a
lowering of the fractional absorption with increasing amounts in the diet. For example, raising
the amount taken in from 7 mg to 36 mg lowered the fractional absorption from 65-75% to 1114%. Unlike Na+ and K+, Mg2+ absorption is clearly subject to regulation at the absorption stage
and mimics calcium. The latter statement is true up to the point where absorption becomes
dependent on calcitriol the active form of vitamin D3. Although calcitriol causes a slight
increase in the amount of magnesium absorbed, no data to support a calcitriol-dependent
mechanism for magnesium absorption.
Even though calcium ions are nearly twice the size of magnesium, calcium still has the
potential to impede the movement of magnesium into the absorbing enterocytes. That
observation infers a common carrier or entry portal for the two divalent cations. Long term
studies, however, dismiss interference between the two, but in the short term the fractional
uptake of Mg2+ is clearly dependent on Ca2+. Nonetheless, a calcium intake must exceed 2,600
mg/day, i.e., nearly two and one-half times the RDA, to disrupt calcium balance. Phosphorus as
phosphate likewise interferes with Mg2+ absorption. As noted for alkaline earth metal ions in
general, this group of metal ions is strongly attracted to phosphate either as the free ion or as a
organophosphate complex . Conversely, magnesium inversely affects phosphate and to a
lesser extent the absorption of calcium.
Competing ions are not the only deterrent. A major deterrent to absorption is phytic
acid from foods rich in fiber in the diet. This compound with its six open phosphate groups has
a strong potential to bind magnesium and prevent is transluminal movement.
Interaction with other Minerals
Magnesium/Calcium
Interactions in Muscle Contraction
The series of reactions that are part of the muscle contraction-relaxation cycle are an
excellent example of the biological synergism between Mg2+ and Ca2+. Although Mg-ATP
bound to the actin-myosin complex provides the energy for the contraction, the contraction
event itself is triggered by Ca2+ bound to troponin C or calmodulin. A second role for Mg2+
comes after the contraction, when it is necessary to restore the relaxation state by removing
Ca2+. Removal is accomplished by both activating a calcium pump that uses Mg-ATP for energy
or by parvalbumin that chelates the Ca2+. Parvalbumin has the property of binding both Mg2+
and Ca2+ at or near the same site on the protein. Therefore, in order to bind Ca2+, the Mg2+
must be displaced by the Ca2+. The Ca2+-Mg2+ exchange rate basically controls the rapidity of
muscle contraction. This perhaps explains why high levels of parvalbumin occur in rapidly
contracting muscles. Not only is Mg-parvalbumin prevalent in resting muscle cells, but the
activation/ relaxation cycle very much depends on Mg2+ ions as well as Ca2+ .
Interaction with Bone Resorption
Bone is particularly sensitive to magnesium/calcium interactions. In a magnesium
deficiency there is the potential to enhance bone loss through resorption. The basis for this
relates to a change in the blood levels of calcium. As noted previously, however, the deficiency
must be rather severe for blood calcium levels to decline.
Magnesium Deficiency
Magnesium deficiency in well-fed infants and adults is a rare occurrence. Even so there
is concern that the diets of most adults are sub-adequate in magnesium. A focus of the
concern is that dietary intake may not be sufficient to maintain magnesium stores in the body.
In those instances where moderate to serve depletion has occurred, the symptoms include:
hypocalcemia
Muscle cramps
Interference with vitamin D metabolism
Neuromuscular hyperexcitability
Tetany
carpal spasm
seizures
Less discernible, but implicated in a magnesium deficiency are:
cardiovascular and neuromuscular diseases
malabsorption syndrome
diabetes mellitus
renal wasting syndrome
osteoporosis
Excessive Intake
A high intake of magnesium from food sources will not cause adverse effects.
Magnesium taken as a pharmacological dose in the form of a salt, however, has this potential.
Large doses of magnesium-containing laxatives and antacids have been associated with
magnesium toxicity. The risk increases with kidney failure. Symptoms under these conditions
include:
Diarrhea (the primary symptom)
Nausea
Abdominal cramps
Difficulty breathing
Metabolic alkalosis
Hypokalemia
Paralytic ileus
Low blood pressure
SUMMARY
Although magnesium bears a close chemical identity with calcium, the two
macrominerals are far apart in the roles played in living systems. Magnesium is a companion to
phosphate and readily forms complexes with ATP and nucleic acids in general. It is a found in
all cells in fairly high amounts but is notable low in blood. Muscle contraction critically depends
on the magnesium content.