Trifunctional enzyme subunit beta, mitochondrial (TP-beta) also known as 3-ketoacyl-CoA thiolase, acetyl-CoA acyltransferase, or beta-ketothiolase is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that in humans is encoded by the ''HADHB''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. HADHB is a subunit of the

mitochondrial trifunctional protein A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...

and has

thiolase Thiolases, also known as acetyl-coenzyme A acetyltransferases (ACAT), are enzymes which convert two units of acetyl-CoA to acetoacetyl CoA in the mevalonate pathway. Thiolases are ubiquitous enzymes that have key roles in many vital biochemi ...

activity.

Structure

The HADHB gene is located on

chromosome 2 Chromosome 2 is one of the twenty-three pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 2 is the second-largest human chromosome, spanning more than 242 million base pairs and representing almost ei ...

, with its specific location being 2p23. The gene contains 17 exons. HADHB encodes a 51.2 kDa protein that is composed of 474

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

; 124

peptides Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Dalton (unit), Da or more are called proteins. Chains of fewer t ...

have been observed through

mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used ...

data.]

Function

This gene encodes the beta subunit of the mitochondrial trifunctional protein, a catalyst of mitochondrial

beta-oxidation In biochemistry and metabolism, beta oxidation (also β-oxidation) is the Catabolism, catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl ...

of long chain

fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...

s. The HADHB protein catalyzes the final step of beta-oxidation, in which 3-ketoacyl CoA is cleaved by the

thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl grou ...

group of another molecule of

Coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the Fatty acid metabolism#Synthesis, synthesis and Fatty acid metabolism#.CE.B2-Oxidation, oxidation of fatty acids, and the oxidation of pyruvic acid, pyruvate in the citric ac ...

. The thiol is inserted between C-2 and C-3, which yields an

acetyl CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized fo ...

molecule and an

acyl CoA Acyl-CoA is a group of CoA-based coenzymes that metabolize carboxylic acids. Fatty acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several equivalents ...

molecule, which is two carbons shorter. The encoded protein can also bind

RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...

and decreases the stability of some

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

s. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the

human genome The human genome is a complete set of nucleic acid sequences for humans, encoded as the DNA within each of the 23 distinct chromosomes in the cell nucleus. A small DNA molecule is found within individual Mitochondrial DNA, mitochondria. These ar ...

in a head-to-head orientation.

Clinical significance

Mutations in this gene, along with mutations in

HADHA Trifunctional enzyme subunit alpha, mitochondrial also known as hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit is a protein that in humans is encoded by the ''HADHA'' gene. Mutation ...

, result in

trifunctional protein deficiency Mitochondrial trifunctional protein deficiency (MTP deficiency or MTPD) is an autosomal recessive fatty acid oxidation disordersubscription needed that prevents the body from converting certain fats to energy, particularly during periods without f ...

. Mutations in either gene have similar clinical presentations. Trifunctional protein deficiency is characterized by decreased activity of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase, and long-chain thiolase. This deficiency can be classified into 3 main clinical phenotypes:

neonatal In common terminology, a baby is the very young offspring of adult human beings, while infant (from the Latin word ''infans'', meaning 'baby' or 'child') is a formal or specialised synonym. The terms may also be used to refer to Juvenile (orga ...

onset of a severe, lethal condition resulting in

sudden infant death syndrome Sudden infant death syndrome (SIDS), sometimes known as cot death or crib death, is the sudden unexplained death of a child of less than one year of age. Diagnosis requires that the death remain unexplained even after a thorough autopsy and ...

(SIDS), infantile onset of a hepatic Reye-like syndrome, and late-adolescent onset of primarily a skeletal

myopathy In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meaning implies that the primary defec ...

. Additionally, some presents showed symptoms associated with myopathy, recurrent and episodic

rhabdomyolysis Rhabdomyolysis (shortened as rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some o ...

, and sensorimotor axonal

neuropathy Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...

. In some cases, symptoms of the deficiency can present as dilated

cardiomyopathy Cardiomyopathy is a group of primary diseases of the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...

, congestive

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...

, and respiratory failure. The deficiency has presented as hydrops fetalis and HELLP syndrome in fetuses. A compound heterozygous mutation of the HADHB gene can cause axonal Charcot-Marie-tooth disease, which is a neurological disorder, which shows that mutations in this gene can result in deficiencies that present in new forms not currently described.

Interactions

HADHB is a functional molecular target of ERα in the mitochondria, and the interaction may play an important role in the

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

-mediated

lipid metabolism Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In ani ...

in animals and humans. Additionally, HADHB has been shown to bind to the distal 3’ untranslated region of renin mRNA, thereby regulating renin protein expression. HADHB and cold-inducible RBP ( CIRBP) were shown to be regulated after

ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...

, positively regulating biogenesis of miR-329 and miR-495.

References

External links