Low-molecular-weight chromium-binding substance (LMWCr; also known as chromodulin) is an

oligopeptide An oligopeptide, often just called peptide ('' oligo-'', "a few"), consists of two to twenty amino acids and can include dipeptides, tripeptides, tetrapeptides, and pentapeptides. Some of the major classes of naturally occurring oligopeptides incl ...

that seems to transport

chromium Chromium is a chemical element with the symbol Cr and atomic number 24. It is the first element in group 6. It is a steely-grey, lustrous, hard, and brittle transition metal. Chromium metal is valued for its high corrosion resistance and hardne ...

in the body. It consists of four amino acid residues;

aspartate Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...

glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...

, and

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...

, bonded with four (Cr³⁺) centers. It interacts with the

insulin receptor The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeo ...

, by prolonging

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

activity through stimulating the

tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...

pathway, thus leading to improved glucose absorption. and has been confused with

glucose tolerance factor Chromium deficiency is described as the consequence of an insufficient dietary intake of the mineral chromium. Chromium was first proposed as an essential element for normal glucose metabolism in 1959, and was widely accepted as being such by the ...

. The exact mechanisms underlying this process are currently unknown. Evidence for the existence of this protein comes from the fact that the removal of ⁵¹Cr in the

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...

exceeds the rate of ⁵¹Cr formation in the

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra. Cel ...

. This indicates that the transport of Cr³⁺ must involve an intermediate (i.e. chromodulin) and that Cr³⁺ is moved from the blood to tissues in response to increased levels of insulin. Subsequent protein isolations in rats, dogs, mice and cows have shown the presence of a similar substance, suggesting that it is found extensively in

mammals Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...

. This oligopeptide is small, having a

molecular weight A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

of around 1 500 g/mol and the predominant

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

present are

aspartic acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...

glutamic acid Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...

, and

. Despite recent efforts to characterize the exact structure of chromodulin, it is still relatively unknown.

Nature of binding

From spectroscopic data, it has been shown that Cr³⁺ binds tightly to chromodulin ( K_f = 10²¹ M⁻⁴), and that the binding is highly

cooperative A cooperative (also known as co-operative, co-op, or coop) is "an autonomous association of persons united voluntarily to meet their common economic, social and cultural needs and aspirations through a jointly owned and democratically-control ...

(

Hill Coefficient In biochemistry and pharmacology, the Hill equation refers to two closely related equations that reflect the binding of ligands to macromolecules, as a function of the ligand concentration. A ligand is "a substance that forms a complex with a bio ...

= 3.47). It has been shown that holochromodulin binds 4 equivalents of Cr³⁺. Evidence for this comes from

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

studies which showed that apochromodulin exerts its maximal activity on

s when titrated with 4 equivalents of Cr³⁺. Chromodulin is highly specific for Cr³⁺ as no other metals are able to stimulate

activity. It is believed to stimulate the

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

of the 3

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...

residues of the β subunits of the insulin receptor. From electronic studies, the

crystal field stabilization energy Crystal field theory (CFT) describes the breaking of degeneracies of electron orbital states, usually ''d'' or ''f'' orbitals, due to a static electric field produced by a surrounding charge distribution (anion neighbors). This theory has been used ...

was determined to be 1.74 x 10³ while the

Racah parameter When an atom has more than one electron there will be some electrostatic repulsion between those electrons. The amount of repulsion varies from atom to atom, depending upon the number and spin of the electrons and the orbitals they occupy. The to ...

B was 847 cm⁻¹. This indicates that chromium binds to chromodulin in the trivalent form. In addition,

magnetic susceptibility In electromagnetism, the magnetic susceptibility (Latin: , "receptive"; denoted ) is a measure of how much a material will become magnetized in an applied magnetic field. It is the ratio of magnetization (magnetic moment per unit volume) to the ap ...

studies have shown that chromium does not

coordinate In geometry, a coordinate system is a system that uses one or more numbers, or coordinates, to uniquely determine the position of the points or other geometric elements on a manifold such as Euclidean space. The order of the coordinates is sign ...

to any

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

amine groups but rather to

carboxylate In organic chemistry, a carboxylate is the conjugate base of a carboxylic acid, (or ). It is an ion with negative charge. Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,...; ''carboxylat ...

s (although the exact the amino acids involved are still unknown). These magnetic susceptibility studies are consistent with the presence of a mononuclear Cr³⁺ center and an unsymmetric trinuclear Cr³⁺ assembly with bridging

oxo ligand A transition metal oxo complex is a coordination complex containing an oxo ligand. Formally O2-, an oxo ligand can be bound to one or more metal centers, i.e. it can exist as a terminal or (most commonly) as bridging ligands (Fig. 1). Oxo ligan ...

s. In chromodulin isolated from bovine liver,

x-ray absorption spectroscopy X-ray absorption spectroscopy (XAS) is a widely used technique for determining the local geometric and/or electronic structure of matter. The experiment is usually performed at synchrotron radiation facilities, which provide intense and tunable ...

studies have shown that the chromium (III) atoms are surrounded by 6 oxygen atoms with an average Cr—O distance of 1.98 Å, while the distance between 2 chromium (III) atoms is 2.79 Å. These results are indicative of a multinuclear assembly. No sulfur ligands coordinate to chromium and instead, it has been proposed that a disulfide linkage between 2

residues occurs owing to a characteristic peak at 260 nm.

References

{{reflist Peptides