Methylmalonyl-CoA mutase Methylmalonyl-CoA mutase (, MCM), mitochondrial, also known as methylmalonyl-CoA isomerase, is a protein that in humans is encoded by the ''MUT'' gene. This vitamin B12-dependent enzyme catalyzes the isomerization of methylmalonyl-CoA to succiny ...

is a mitochondrial homodimer apoenzyme (EC. 5. 4.99.2) that focuses on the catalysis of

methylmalonyl CoA Methylmalonyl-CoA is the thioester consisting of coenzyme A linked to methylmalonic acid. It is an important intermediate in the biosynthesis of succinyl-CoA, which plays an essential role in the tricarboxylic acid cycle (aka the Citric Acid Cyc ...

to succinyl CoA. The enzyme is bound to adenosylcobalamin, a hormonal derivative of

vitamin B12 Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. ...

in order to function. Methylmalonyl-CoA mutase deficiency is caused by genetic defect in the MUT gene responsible for encoding the enzyme. Deficiency in this enzyme accounts for 60% of the cases of

methylmalonic acidemia Methylmalonic acidemia, also called methylmalonic aciduria, is an autosomal recessive metabolic disorder that disrupts normal amino acid metabolism. It is a classical type of organic acidemia. The result of this condition is the inability to prope ...

Symptoms

People with methylmalonyl CoA mutase deficiency exhibit many symptoms similar to other diseases involving

inborn errors of metabolism Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances ( substra ...

. Newborn babies experience with vomiting,

acidosis Acidosis is a process causing increased acidity in the blood and other body tissues (i.e., an increase in hydrogen ion concentration). If not further qualified, it usually refers to acidity of the blood plasma. The term ''acidemia'' describe ...

hyperammonemia Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to brain injury and death. It may be primary or secondary. Ammonia is a substance that contains nitrogen. I ...

hepatomegaly Hepatomegaly is the condition of having an enlarged liver. It is a non-specific medical sign having many causes, which can broadly be broken down into infection, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdo ...

(enlarged livers), hyperglycinemia (high

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 proteinog ...

levels), and

hypoglycemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose bel ...

(low blood sugar). Later, cases of

thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients a ...

and

neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteri ...

can occur. In some cases intellectual and developmental disabilities, such as

autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...

, were noted with increased frequency in populations with methylmalonyl-CoA mutase deficiency.

Causes

Although methylmalonic acidemia has a variety of causes, both genetic and dietary, methylmalonyl CoA mutase deficiency is an autosomal recessive genetic disorder. Patients with the deficiency either have a complete gene lesion, designated as mut0 or a partial mutation in the form of a frameshift designated as mut-. This frameshift affects the folding of the enzyme rendering its binding domain less effective. Patients with a complete deletion have an inactivation of methylmalonyl CoA mutase and exhibit the most severe symptoms of the deficiency, while patients with a partial mutations have a wide range of symptoms. Over 49 different mutations have been discovered for the MUT gene, yet only two appear in any discernible frequency.

Enzymatic activity

Methylmalonyl-CoA mutase catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA, and uses a B12 derived prosthetic group, adenosylcobalamin, in order to accomplish this transfer. The enzyme is a homodimer, located in the mitochondrial matrix. The enzyme is 750 amino acids long, with the a metal ligand binding region to bind to the Cobalt region of adenosylcobalamin. The enzyme works by cleaving the adenosylcobalamin C-Co(III) bond, giving the carbon and cobalt (III) atoms each an electron. The cobalt then fluctuates between its two oxidation states: Co(II) and Co(III). In this way the adenosylcobalamin works as a reversible free radical generator. The cobalt therefore donates an electron back to the methylmalonyl-CoA backbone in order to transfer the coenzyme A group.

Metabolic activity

Methylmalonyl-CoA mutase is essential to the degradation pathways of many molecules including amino acids, and

odd-chain fatty acid Odd-chain fatty acids are those fatty acids that contain an odd number of carbon atoms. In addition to being classified according to their saturation or unsaturation, fatty acids are also classified according to their odd or even numbers of consti ...

s. Methylmalonyl-CoA mutase links the propionyl-CoA degradation byproduct of these macromolecules to the tricarboxylic acid cycle. For amino acid metabolism, methylmalonyl-CoA mutase works in the degradation pathways of

isoleucine Isoleucine (symbol Ile or I) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depr ...

threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO� ...

valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotona ...

, and

methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ...

propionyl-CoA Propionyl-CoA is a coenzyme A derivative of propionic acid. It is composed of a 24 total carbon chain (without the coenzyme, it is a 3 carbon structure) and its production and metabolic fate depend on which organism it is present in. Several diffe ...

and undergoes the same metabolism previously described for propionyl-CoA. The cholesterol superpathway follows the degradation of cholesterol down to various substrates, however only a couple of these biotransformed molecules see propionyl-CoA as a byproduct. The conversion of 3,24-dioxocholest-4-en-26-oyl-CoA to 2-oxochol-4-en-24-oyl-CoA sees the release of a propionyl-CoA molecule. Additionally, the conversion of 3-oxo-23,24-bisnorchol-4-en-17-ol-22-oyl-CoA to androst-4-ene-3,17-dione release of a propionyl-CoA molecule. Finally, the degradation of (S)-4-hydroxy-2-oxohexanoate to pyruvate and propanal, in turn releases a propionyl-CoA substrate after the propanal is converted. All these propionyl-CoA substrates are converted to succinyl-CoA following the methylmalonyl pathway For amino acid metabolism, methylmalonyl-CoA mutase works in the degradation pathways of

, and

. These amino acids are degraded into propanoyl-CoA which is then further degraded into (S)-methylmalonyl-CoA. This substrate must be further metabolized by a very similar enzyme, methylmalonyl-CoA epimerase, which converts the (S) form of methylmalonyl-CoA into the (R) form. This is finally transformed using methylmalonyl-CoA mutase. L-methionine is also metabolized through a longer superpathway (see Figure 2). After transformation to L-homocystein, it is combined with L-serine to make L-cystathione, which is hydrolyzed by cystathione gamma lyase to create 2-oxobutanoate. This substrate is transformed to propanoyl-CoA and undergoes the same metabolism previously described for propanoyl-CoA. Odd chain fatty acids are also metabolized through the methylmalonyl pathway. The degradation of odd chain fatty acids releases Acetyl-CoA and propionyl-CoA. Propionyl-CoA is then converted to succinyl-CoA, and both succinyl-CoA and propionyl-CoA are interjected into the tricarboxylic acid cycle for continued production of reductant.

Metabolic pathology

The final product of methylmalonyl-CoA mutase activity is succinyl-CoA which is a tricarboxylic acid cycle substrate. A side effect of excess methylmalonyl-CoA is an interruption of the enzymes responsible for other transformations earlier in the metabolism of propionyl-CoA, leading to propanoic acidemia as well. Excess methylmalonyl-CoA leads to oxidative stress by inhibiting the methylation pathway and formation of glutathione, which is dependent on that pathway. This disrupts the biosynthesis of myelin, urea, and glucose. Specifically, excess methylmalonyl-CoA places oxidative stress on the mitochondrial enzymes involved in the urea cycle (such as ammonia-dependent-carbamoyl-phosphate synthase or CPS1), and inhibits its mechanism of action. The combination of inhibited urea synthesis and poor protein metabolism, as well as a weakly replenished tricarboxylic acid cycle contribute to the symptoms of methylmalonic acidemia.

Diagnosis

Several tests can be done to discover the dysfunction of methylmalonyl-CoA mutase. Ammonia test, blood count, CT scan, MRI scan, electrolyte levels, genetic testing, methylmalonic acid blood test, and blood plasma amino acid tests all can be conducted to determine deficiency.

Treatment

There is no treatment for complete lesion of the mut0 gene, though several treatments can help those with slight genetic dysfunction. Liver and kidney transplants, and a

low-protein diet A low-protein diet is a diet in which people decrease their intake of protein. A low-protein diet is used as a therapy for inherited metabolic disorders, such as phenylketonuria and homocystinuria, and can also be used to treat kidney or liver dis ...

all help regulate the effects of the diseases.

Prognosis

Infant mortality is high for patients diagnosed with early onset; mortality can occur within less than 2 months, while children diagnosed with late-onset syndrome seem to have higher rates of survival. Patients with a complete lesion of mut0 have not only the poorest outcome of those with methylaonyl-CoA mutase deficiency, but also of all individuals with any form of methylmalonic acidemia.

References

External links

* * {{DEFAULTSORT:Methylmalonyl-Coa Mutase Deficiency Amino acid metabolism disorders