biochimie anorganica

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Inorganic BiochemistryRobert J. P. WilliamsUniversity of Oxford, Oxford, UK

All organisms require a limited, selected number of chemical

elements. The requirement includes obviously the nonmetal

elements H, C, N, O, P, and S which provide the vast majority

of elements in organic compounds in every cell. Other elements

which are necessary for organisms include Na, K, Mg, Ca, Mn,

Fe, (Co), (Ni), (Cu), Zn, Mo or W, Cl, B, and Se. Those in

parentheses are essential for most organisms. Inorganic

biochemistry therefore includes the modes of uptake, the

ways of incorporation, and the functional value of these

essential elements. It also includes consideration of elements aspoisons and as valuable drugs in medical practice.

Introduction

A glance at the periodic table, Figure 1, shows that of the18 groups in the table, elements have been selected byorganisms from 15 groups, indicating that life is based onalmost the full diversity of the chemistry of the periodictable. Absent are elements from groups 4, 13, and 18.There are also organisms which use F, Si, Sr, Ba, V, Cd,and possibly Sn. Thus of the common elements there areonly a few that are not found in some living system, e.g.,Al and Ti, while most of the uncommon elements, i.e.,elements heavier than Zn,are absent.This gives rise to thepossibility for the use by man in attacking medical andagricultural problems of several inorganic elements asaccidental or deliberate poisons or medicines. Examplesare Be, Al, Br, Pt,Hg, Au,Sb, Bi, and Pb. It is the study of all the elements, often but not always in combinationwith the elements of organic chemistry that is called“inorganic chemistry,” and when applied in a livingsystem it is called “inorganic biochemistry” or “biologi-cal inorganic chemistry.” In what follows, attention isdrawn to the value of certain of these elements starting

from the most common in all organisms, but it is clearthat together organic and inorganic elements, some15– 20 in all, created life as we know it.

Electrolytes

All cells are required to manage the ions of those elementswhich are highly available in the environment and aremainly free, namely, Naþ, Kþ, Mg2þ, Ca2þ, and Cl2.

Especially Naþ, Kþ, and Cl2 are rarely combined withorganic or inorganic molecules or anions. These fiveelements have always dominated the sea as electrolytesbut have been and are present at much lower concen-trations in all freshwater. All cells need to control theuptake of these ions for they are serious components of the ionic strength and osmotic pressure inside as well asoutside cells and they are major units in electrolyticcharge balance in all natural fluids. It is found that cells

have, possibly universally, a free ion cytoplasmicconcentration of Naþ (1022 M), Kþ (1021 M), Mg2þ

(1023 M), Ca2þ (,1026 M), Cl2 (1023 M). Clearly lifein the sea rejects Naþ, Mg2þ, Ca2þ, and Cl2while takingin Kþ but life in freshwater, which evolved later, has totake in all five elements. The above functional value of Naþ, Kþ,andCl2, the most available and which bind theleast to organic matter, evolved from the use in simpleelectrolyte balances to include employment in bioener-getic exchanges across membranes and more recently todominate electrolytic messages. Here particularly Naþ,Kþ, Cl2, and now including Ca2þ are the only simpleionic current carriers of such cells as nerves and muscles

and are essential components of the functioning of thebrain.Text books on physiology to a great degree concernmainly these five elements.

Calcium is the most strongly rejected of all five butalso functions as a bound element especially in cellactivation of higher cellular organisms. Magnesium is notrejected strongly from any cell and is an essential weakacid catalyst. It is present in most of the reactions of phosphates including ATP42, which is,50% MgATP22

in cells. Examples of its functions are kinases and it is avital structural component of RNA and DNA. Mg2þ andCa2þ together help to stabilize cell membranes and wallsand are present in most biological minerals such as shells

and bones.Magnesium has a quite exceptional additional func-

tion in chlorophyll, the light-harvesting and light-activating factor of virtually all plant life.

Iron

The next most common metal element is iron. It is verylargely bound to proteins not free in cells. It was very

Encyclopedia of Biological Chemistry, Volume 2. q 2004, Elsevier Inc. All Rights Reserved. 417



readily available from the primitive reducing sea asferrous ion but, as oxygen pressure rose more than twobillion years ago, iron became ferric ions in solutionwhich precipitated and availability became veryreduced. As a consequence all aerobic organisms havecleverly devised scavenging systems for iron. Theessential nature of the element derives from its use as acatalyst. In its protein combinations it is found bound iniron–sulfur proteins, in heme proteins, and in proteinsbound simply to nitrogen and oxygen side chains. Theseproteins are largely engaged in oxidation or reductioncatalysts, in the transport of electrons, as carriers(hemoglobin and myoglobin), as sensors for CO, NO,

and O2, in DNA synthesis from RNA, and as storagebuffers for iron. There is in fact a very extensive networkof iron proteins essential in all cells but very noticeablein the bioenergetics of both chloroplasts and mitochon-dria. There is for this metal element a series of concentration controls linked through transcriptionfactors to DNA. It may be that the overall expressionof many functional parts of a cell are linked to theconcentration of free ferrous ions in the cell cytoplasm.However, the storage of iron is in a ferric ion precipitatebound in a protein, ferritin.

Zinc

Next to iron in importance amongst trace elements iszinc. Unlike iron it was restricted in its availability toprimitive life since it has an insoluble sulfide. As sulfur,in the form of H2S, became oxidised to sulfate, so zincwas liberated, and it is now quite a common element inthe sea. Zinc is not like iron in its functions. It does nottake part in oxidation or reduction reactions but is a

good acid catalyst. Hence it finds use in organicchemistry as well as in organisms. In cells its acidicfunction is used not only in a wide range of degradativeenzymes – peptidases, nucleases, and saccharases, andin hydration reactions – but also in RNA/DNAsynthetases. Zinc has a distinct role in the nucleus of eukaryotes in proteins called zinc fingers, which act astranscription factors especially involving sterol, thyrox-ine, retinoic acid, and related hormones. Thus, it isimportant in homeostasis and in organism metamorphictransformations such as the transition through puberty.There is now strong evidence that free zinc, normallyvery low in cells, is used at considerable concentrations

in certain parts of the brain as a transmitter and in thereproductive tract of males. As is the case for iron theremay be no life without zinc.

Copper

Copper is probably not a universal requirement for life.The sulfides of copper are extremely insoluble andprimitive anaerobic archaea probably did not use it.Later oxidation of sulfide generated available copperand in general aerobes employ it as an oxidative catalyst.This use is mainly confined to extracellular or periplas-mic compartments of cells since free copper itself is verypoisonous internally, where it is probably no more than10215 M. The locations of the sites of action of copperproteins contrast strongly with those of iron as seen inthe different cell compartments in which the two areused. A particular function of copper is in the cross-linking of extracellular matrices which helps to stabilizemulticellular organisms e.g. the final forms of collagen,lignin, and chitin. The homeostasis of copper in cells

FIGURE 1 The periodic table of the elements showing those essential for most organisms and those required by some organisms. Note thedistribution of required elements within the periodic table.

418 INORGANIC BIOCHEMISTRY



appears to be managed by a class of proteins,metallothineins, which also control the levels of freezinc. Uptake and rejection of copper requires cellularpumps and several disadvantageous inherited conditionsarise from mutations in these pumps.

Cobalt

The requirement for cobalt in organisms is unusuallydistributed. It is most commonly found in vitamin B12,yet advanced plants do not have this compound – avitamin in higher animals and also essential in primitiveanaerobes. Apart from its function in some ribonucleo-tide reductases vitamin B12 is required in severalenzymes controlling rearrangement reactions especiallyof sugars. This vitamin is needed in smaller amountsthan any of the other vitamins.

Manganese

The requirement for manganese, a relatively abundanttrace element, is due to its major involvement in twokinds of enzymes, glycosylases and oxygen productionunits. The production of oxygen is confined to plants butit was the evolution of this reaction, initially in single cellanaerobes to obtain hydrogen from water, which causedthemajor steps of biological advancement over billions of years. The present-day level of some 20% oxygen in theatmosphere is entirely due to the activity of manganeseenzymes. Some enzymes statedto require manganesemayin fact be magnesium proteins in vivo since manganesereadily replaces magnesium functions in vitro.

Nickel

Nickel, although it is available, is a rare element in allorganisms being most common in primitive anaerobes.There it occurs in hydrogenases as a multimetal complexwith iron and in the coenzyme F-430 which like heme,chlorophyll, and vitamin B12 is synthesized from uropor-phyrin. Although nickel is used in urease, especially inplants, it has no functional protein coded in the DNA of higher animals such as man. Even so nickel is required inman since it is utilized by some of the lower organisms

which inhabit the digestive tract of man where they aiddegradation. A feature of evolution is the decline in theuse of nickel and cobalt with a steady use of iron and anever-increasing involvement of zinc and copper.

Molybdenum

Molybdenum is present in the sea in considerableconcentration. It would appear that it is essential for

all life except some very primitive anaerobes where itsfunction is replaced by tungsten. The most obvious useof molybdenum is in nitrogen fixing bacteria, symbiotsof plant life. Plants and animals cannot fix nitrogen gas.In these higher organisms molybdenum is required in avariety of oxygen-atom transfer reactions includingenzymes for nitrate, sulfate, and carboxylate substrates.Note that the requirement for molybdenum for fixation

of nitrogen gas and for reduction of nitrate implies thatvirtually all sources of the element nitrogen for organicsynthesis in cells are dependent upon this element. Thefact that these enzymes are found in prokaryotes, nothigher organisms, stresses the nature of life as belongingto an ecosystem. Many diseases are associated withdeficiency of the element especially in cattle.

Selenium

The importance of this element in all organisms is oftenmissed despite the fact that it is the only heavy element

which is part of a coded amino acid, seleno-methionine.This nonmetal is also found in seleno-cysteine. Thefunctions of selenium are very different in anaerobeswhere it acts as a metal ligand from those in higherorganisms where it is part of a powerful antioxidant –peroxidase. The switch in function follows the change of availability of the element from hydrogen selenide inprimitive seas to selenate today, compare the chemicalchange of sulfur. It is thought that low levels of seleniumin the human diet are responsible for many diseases, forexample, of the heart. Selenium is now added as asupplement in some foods and to some soils.

Iodine

Iodine is found in the hormone, thyroxide, which is ahormone responsible for some features of growthcontrol. The use of the element appears later inevolution. Iodine deficiency is a well-known geneticdisease associated with goitre. Once again iodine is notused in lower organisms. Note that bromine and fluorineare little used in any organism so that iodine, fluorine,and bromine are quite unlike chlorine as chloride inbiological organisms.

Rare Uses of Inorganic Elements

There are a variety of organisms in which mineralscontain metals other than calcium and nonmetals otherthan carbonate (shells), phosfate (bone), or oxalate inplants. They include strontium and barium sulfates,which because of their density cause cells to settle inwater and are useful as gravity sensors; calcium fluoride

INORGANIC BIOCHEMISTRY 419



in krill; various iron oxides in teeth and in magneticsensors; and silica especially in diatoms and some plants.

Suggestive evidence is now available showing thatcadmium may well be essential in a few lowly organismsand increasingly it is believed that chromium may be afactor in combating diabetes. There is clear evidence forthe requirement of arsenic, boron, vanadium, andquestionable evidence concerning some heavier

elements, in selected organisms.

Inorganic Elements in Medicines

and Poisons

Apart from the obvious uses in poisons and drugs of theabove essential elements in organic derivatives unknownto living systems, there are many uses of other inorganicelements as both medicines and poisons. Of course, wemust be careful with the use of these words, “drugs” and“poisons,” since the use of medical drugs is dependent

on dose where excess of a drug becomes a poison.Historically in medical practice inorganic elements werein fact used extensively before they were thought to domore harm than good. The uses of mercury, evenmercury amalgam in teeth fillings, were considerablebut mercury compounds are not recommended today.However, today, surprisingly, there are medicines usingamongst other elements lithium, platinum, gold, andbismuth as well as technecium in diagnostics. It isanticipated that there will be many more uses of nonessential as well as those of essential elements inthe not too distant future. In agricultural procedureseveral antifungal agents contain copper or mercury

to this day.

The Selection of Elements by Cells

Given that only a limited number of elements arerequired and must be accumulated by organisms from afree condition in the environment, many unwantedelements must be screened against or have to be rejectedsince they are poisons, e.g., Al, while many have to besomewhat rejected but used, Na, Cl, Ca, Cu, Ni, and Co,for example, while some have to be concentrated, forexample, C, N, P, S, Se, and K and others fromorganisms living in fresh water. Selection is thereforerequired at cell membranes by outwardly or inwardlydirected pumps and also by binding. The principles of selection are well understood chemically. Such activityrequires energy and here one other element is of dominant interest, hydrogen as the proton, in the formof Hþ gradients which make ATP for use in pumps foruptake and rejection of elements, and generally in

many biological activities such as synthesis and mech-anical action.

Conclusion

Today it is clearly obvious that living systems are notjust composed of organic chemicals although the major

bulk of them are of the conventional light nonmetals.Other elements, mainly metals, are involved inessential roles from maintaining cell stability and incommunication networks to catalysis. The interactionof the system life/environment is therefore extremelycomplicated.

SEE A LSO THE FOLLOWING A RTICLES

Chloroplasts † Heme Proteins † Heme Synthesis †

Iron–Sulfur Proteins † Vitamin B12 and B12-Proteins †Zinc Fingers

GLOSSARY

abundance The quantitative amount of an element in the universe or

on the surface of Earth.

availability A measure of the quantity of elements to whichorganisms have access ranging from easily available such as sodium

and potassium to available with difficulty such as iron today.

essential Describing or referring to a requirement for an elementwithout which the organism would show extreme abnormality or

even not exist.

FURTHER R EADING

Bertini, I., Gray, H. B., Lippard, S. J., and Valentine, J. S. (1994).Bioinorganic Chemistry. University Science Books, Mill Valley,California.

Frau ´ sto da Silva, J. J. R., and Williams, R. J. P. (2001). The Biological

Chemistry of The Elements. 2nd edition. Oxford University Press,Oxford.

Kaim, W., and Schwederski, B. (1994). Bioinorganic Chemistry:

Inorganic Elements in the Chemistry of Life. Wiley, Chichester.

Lippard, S. J., and Berg, J. M. (1994). Principles of Bio-Inorganic Chemistry. University Science Books, Mill Valley,California.

Messerschmidt, A., Huber, R., Poulos, T., and Wieghardt, K. (eds.)(2001). Handbook of Metalloproteins, Vols 1 and 2, Wiley,Chichester.

BIOGRAPHY

R. J. P. Williams is an Emeritus Professor at Oxford University, UK. Heis sometimes referred to as the “grandfather” of bioinorganic

chemistry, because he initiated the detailed study of the selectiveinteraction of inorganic elements with organic compounds. His major

work has been on heme-, zinc-, and copper-containing enzymes as wellas on theuse of calcium and magnesium in cells.He proposed the useof

proton gradients in the synthesis of ATP.

420 INORGANIC BIOCHEMISTRY

biochimie anorganica

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