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Metal regulation of metabolism

Arnold J Bloom

A broad range of biochemicals, from proteins to nucleic acids, Metals exist in several distinct pools within cells. For

function properly only when associated with a metal, usually a example, manganese in chloroplasts may belong to (a)

2+ 2+

divalent cation. Not any divalent metal will do: these metals ‘free ionic’ Mn , (b) ‘weakly bound’ Mn that is remov-

differ in their ionic radius, dissociation in water, ionization able by EDTA, (c) ‘strongly bound’ Mn that is involved in

potential, and number of unpaired electrons in their outer water oxidation, and (d) ‘very strongly bound’ Mn that

shells, and so substituting one metal for another often changes serves in the stacking of the chloroplast lamellae [7,8].

substrate positioning, redox reactivities, and physiological Activity of a metal is its ‘effective concentration’ in a

performance, and thus may serve as a regulatory mechanism. solution containing a mixture of compounds; that is, the

For instance, exchanging manganese for magnesium in several chemical potential of the metal depends on its activity in

chloroplast enzymes maintains plant carbon-nitrogen balance a real solution in the same manner that its chemical

under rising atmospheric CO2 concentrations. Here, we review potential depends on concentration in an ideal solution.

this and a few other cases where association of proteins or Only ‘free ionic’ and ‘weakly bound’ metals contribute

nucleic acids with different metals control metabolism. significantly to the activity of a metal.

Address Cells regulate activities of metals (aMe’s) in reverse order

Mail Stop 3, Department of Plant Sciences, University of California at to that of affinities for them [9,10] (Table 1):

Davis, Davis, CA 95616-8780, United States

2+ 2+ 2+ 2+ 2+ 2+ 2+

aMg > aMn > aFe > aCo > aNi > aZn > aCu .

Current Opinion in Chemical Biology 2019, 49C:33–38 2+

Cellular activities range from Mg whose the activity is

2+

This review comes from a themed issue on Bioinorganic chemistry high enough to be considered a macronutrient, to Cu

Edited by Kyle M Lancaster whose activity averages less than one atom per cell [11].

With affinities and activities trending in opposite direc-

tions, dissociation constants (Kd’s) become roughly equal

https://doi.org/10.1016/j.cbpa.2018.09.017 to the activities of the metals, and the interactions

1367-5931/ã 2018 Elsevier Ltd. All rights reserved. between biochemicals and metals become relatively fast

and loose. This is because if a biochemical B associates

2+

with a metal Me on a one-to-one basis (i.e. BMe $ B +

2+

Me ), the dissociation constant of the reaction is defined by

Introduction aBaMe2þ

Kd ¼ :

Biochemicals, including many proteins and nucleic aBMe

acids, form complexes with divalent cation metals that

allow the biochemicals to achieve bond angles and redox 2+

When aMe = Kd, then aB = aBMe ; in words, the activities

potentials that cannot be realized by polypeptides and

of the unassociated and metal-associated biochemical are

nucleotides alone. Indeed, nearly half of all enzymes 2+

the same when the Me activity equals Kd. Under such

require metals in their active sites to perform catalysis

conditions, the metal relatively rapidly associates with

[1]. Nucleic acids, in that they contain negatively

and disassociates from the biochemical [12]. This pre-

charged phosphate groups at physiological pH, employ

sents a major problem: techniques employed for isolating

divalent metals as counter-ions [2].

a specific biochemical often displace the associated metal,

and so determining which metal is associated in vivo

The stability of divalent metals-biochemical com-

becomes difficult.

plexes—in terms of the binding affinity of the aqueous

metal for the biochemical ligand when it replaces water—

2+ 2+ Binding sites within proteins and nucleic acids may

increases from Mg to Cu according to the expanded

physically accommodate different metals because these

Irving-Williams series [3–6]:

metals not only have the same charge, but also exhibit

2+ 2+ 2+ 2+ 2+ 2+ 2+ similar ionic radii in aqueous solutions (Table 1). Displa-

Mg < Mn < Fe < Co < Ni < Cu > Zn .

cing one metal with another, however, may change the

2+

The exact location of Zn in this series is uncertain, lying chemistry of the biochemical including the pKa of the

2+ 2+

somewhere lower than Cu , but higher than Co . metal/H2O complex (Table 1), ionization potential

www.sciencedirect.com Current Opinion in Chemical Biology 2019, 49:33–38

34 Bioinorganic chemistry

Table 1

Some properties of divalent cation metals. “Ionic radius, low spin” designates that the metal ion has as many of its electrons paired as

2+ + +

possible. “pKa metal/H2O complex” designates the reaction [Me(H2O)6] ! [Me(H2O)5OH] + H . “Ionization potential” designates the

2+

energy required to remove electrons from the metal, Me to Me , and reflects the Lewis base strength

2+ 2+ 2+ 2+ 2+ 2+ 2+

Metal Mg Mn Fe Co Ni Cu Zn Reference

–6 –6 –15 –9

Cytosolic activity (mM) 0.8 0.01 0.005 10 10 10 10 [9]

˚

Ionic radius (A), low spin 0.65 0.67 0.61 0.65 0.69 0.69 0.71 [28]

pKa metal/H2O complex 11.2 11.0 9.5 9.7 9.9 8 9.9 [38]

Ionization potential (eV) 15.04 15.64 16.18 17.06 18.17 20.29 17.96 [1,39]

(Table 1), redox reactivity, ligand binding, or binding another example of ‘one protein, two enzymes’. Rubisco

geometry. Such changes can render a protein or nucleic catalyzes either carboxylation of the substrate RuBP to

acid nonfunctional leading to physiological disorders initiate the C3 carbon fixation pathway or oxidation of RuBP

including neurodegenerative diseases [13]. to initiate the photorespiratory pathway (Figure 1b). The

balance between the carboxylation and oxygenation reac-

Beneficial metal substitutions tions depends on several factors, but the one that has been

Not all metal substitutions are deleterious. For example, ignored is the extent to which Rubisco associates with either

2+ 2+ 2+ 2+ 2+

Mn and Fe bind relatively weakly to proteins or Mg or Mn . When Rubisco associates with Mn , carbox-

nucleic acids and prefer similar coordination environ- ylation and oxidation proceed at similar rates (Table 2) [20],

ments; therefore, proteins or nucleic acids have difficulty the oxygenation produces singlet oxygen [21,22], and the

2+

in distinguishing between these metals on the basis of Mn transfers an electron with every oxidation [22]. When

2+

structure alone [14 ]. Yet the redox chemistry of the two Rubisco associates with Mg , carboxylation accelerates and

metals are highly disparate, and aerobic organisms may proceeds about four times faster than oxidation (Table 2),

2+ 2+

substitute Mn for Fe in proteins to avoid oxidative but no electrons are transferred [23].

damage and iron deficiencies [14 ]. In Escherichia coli,

2+

several enzymes that use Fe to bind substrate and to Carboxylation of RuBP when Rubisco associates with

2+

D H

stabilize electrostatically an oxyanionic intermediate suf- Mg results in a reaction enthalpy change ( r ) of

–1

fer damage when exposed to oxidative stress agents such 21 kJ mol , whereas oxygenation of RuBP when

2+

D H

as H2O2 and O2 that the bacterium may normally Rubisco associates with Mn results in a r of

–1

encounter [15]. Under oxidative stress, E. coli activates 319 kJ mol , more than 15 times greater [24]. The

2+

a transcriptional regulator that upregulates Mn import prevailing view is that the initial reaction of the photo-

2+ 2+ 2+

!

and Fe sequestration, and thus, Mn replaces of Fe respiratory pathway is RuBP + O2 + H2O glycolate + 3-

within these enzymes and they are able to sustain near phosphoglycerate + Pi and that the energy released during

normal activity [15]. RuBP oxidation is dissipated as waste heat [24].

Another example of a beneficial metal substitution is the We proposed an alternative pathway [25 ] in which the

2+

enzyme acireductone dioxygenase (ARD), which is part electrons transferred byMn duringtheoxidation ofRuBP

+

of the methionine salvage pathway in the bacterium reduce NADP to NADPH, and so the initial reaction of

Klebsiella oxytoca in which it catalyzes two different reac- photorespiration becomes

2+ 2+ + +

! tions depending on whether Fe or Ni occupies the RuBP + NADP + H + O2 + H2O pyruvate + glycolate-

2+ 2+

active site [16]. When associated with Fe , ARD cata- + NADPH + 2Pi. Next, Mn -malic enzyme catalyzes the

!

lyzes the reaction in which acireductone and dioxygen reaction pyruvate + CO2 + NADPH

+

generate formate and the ketoacid precursor of methio- malate + NADP . Together, the net result becomes

!

nine, 2-keto-4-methylthiobutyrate (KMTB) (Figure 1a). RuBP + O2 + CO2 + H2O glycolate + malate + 2Pi

2+

When associated with Ni , the enzyme catalyzes the (Figure 1b). The additional malate generated by this

reaction in which the same substrates generate alternative pathway empowers many energy-intensive bio-

methylthiopropionate (MTB), carbon monoxide, and for- chemical reactions such as those involved in nitrate assimi-

mate (Figure 1a). ARD is promiscuous and also forms lation. Thus, photorespiration may be much more energy

2+ 2+ 2+

associations with Co or Mn that promote a Ni -like efficient than most researchers have presumed [25 ].

2+ 2+

reaction or with Mg that promote a low level Fe -like

2+ 2+

reaction [17]. How the dual chemistry of the ARD We recently quantified Mg and Mn activities in

2+

enzyme serves to regulate the methionine salvage path- isolated tobacco chloroplasts [20]. Mg was more active

2+ 2+ 2+

a a m

way is still unknown [18 ]. than Mn ( Mg 3 mM versus Mn 20 M). The

activities in the chloroplasts were roughly proportional to

Rubisco (ribulose-1,5-bisphosphate carboxylase/oxyge- the concentrations in the medium, indicating that regu-

nase), the most prevalent protein on the planet [19], provides lation of metal activities occurred at the cellular level

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