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 Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

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

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. Mutations in ''HADHA'' have been associated with

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 fo ...

long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency is a rare autosomal recessive fatty acid oxidation disorder that prevents the body from converting certain fats into energy. This can become life-threatening, particularly during perio ...

Structure

HADHA is an 82.9 kDa protein composed of 763 amino acids. The

mitochondrial 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 use ...

membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the alpha subunit catalyzing the 3-hydroxyacyl-CoA dehydrogenase and

enoyl-CoA hydratase Enoyl-CoA hydratase (ECH) or crotonase is an enzyme that hydrates the double bond between the second and third carbons on 2-trans/cis-enoyl-CoA: ECH is essential to metabolizing fatty acids in beta oxidation to produce both acetyl CoA and e ...

activities. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation.

Function

This gene encodes the alpha subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial

beta-oxidation In biochemistry and metabolism, beta-oxidation is the 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, which enters the citric acid cycle, ...

of long chain fatty acids. The enzyme converts medium- and long-chain 2-enoyl-CoA compounds into the following 3-ketoacyl-CoA when NAD is solely present, and

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 for ...

when NAD and CoASH are present. The alpha subunit catalyzes this reaction, and is attached to

HADHB Trifunctional enzyme subunit beta, mitochondrial (TP-beta) also known as 3-ketoacyl-CoA thiolase, acetyl-CoA acyltransferase, or beta-ketothiolase is an enzyme that in humans is encoded by the ''HADHB'' gene. HADHB is a subunit of the mitochondri ...

, which catalyzes the last step of the reaction.

Clinical significance

Mutations in this gene result in trifunctional protein deficiency or

. The most common form of the mutation is G1528C, in which the

guanine Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is called ...

at the 1528th position is changed to a

cytosine Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine (uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached (an am ...

. The gene mutation creates a protein deficiency that is associated with impaired oxidation of

long-chain fatty acids In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...

that can lead to sudden infant death. Clinical manifestations of this deficiency can include

myopathy In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness. ''Myopathy'' means muscle disease (Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meani ...

cardiomyopathy Cardiomyopathy is a group of diseases that affect 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 ...

, episodes of

coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to respond normally to painful stimuli, light, or sound, lacks a normal wake-sleep cycle and does not initiate voluntary actions. Coma patients exhi ...

, 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 belo ...

. Long-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency is associated with some pregnancy-specific disorders, including

preeclampsia Pre-eclampsia is a disorder of pregnancy characterized by the onset of high blood pressure and often a significant amount of protein in the urine. When it arises, the condition begins after 20 weeks of pregnancy. In severe cases of the disease ...

HELLP syndrome HELLP syndrome is a complication of pregnancy; the acronym stands for hemolysis, elevated liver enzymes, and low platelet count. It usually begins during the last three months of pregnancy or shortly after childbirth. Symptoms may include feelin ...

(hemolysis, elevated liver enzymes, low platelets),

hyperemesis gravidarum Hyperemesis gravidarum (HG) is a pregnancy complication that is characterized by severe nausea, vomiting, weight loss, and possibly dehydration. Feeling faint may also occur. It is considered more severe than morning sickness. Symptoms often get ...

, acute fatty liver of pregnancy, and maternal floor infarct of the placenta. Additionally, it has been correlated with

Acute fatty liver of pregnancy Acute fatty liver of pregnancy is a rare life-threatening complication of pregnancy that occurs in the third trimester or the immediate period after delivery. It is thought to be caused by a disordered metabolism of fatty acids by mitochondria in ...

(AFLP) disease. From a clinical perspective, HADHA might also be a useful marker to predict resistance to certain types of

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

in patients with

lung cancer Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissue (biology), tissues of the lung. Lung carcinomas derive from tran ...

Interactions

HADHA has been shown to have 142 binary protein-protein interactions including 117 co-complex interactions. HADHA appears to interact with

GABARAP Gamma-aminobutyric acid receptor-associated protein is a protein that in humans is encoded by the ''GABARAP'' gene. Function Gamma-aminobutyric acid A receptors ABA(A) receptorsare ligand-gated chloride channels that mediate inhibitory neurot ...

MAP1LC3B Microtubule-associated proteins 1A/1B light chain 3B (hereafter referred to as LC3) is a protein that in humans is encoded by the ''MAP1LC3B'' gene. LC3 is a central protein in the autophagy pathway where it functions in autophagy substrate selec ...

TRAF6 TRAF6 is a TRAF human protein. Function The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from members of the TNF recept ...

GABARAPL2 Gamma-aminobutyric acid receptor-associated protein-like 2 is a protein that in humans is encoded by the ''GABARAPL2'' gene. Interactions GABARAPL2 has been shown to interact with ULK1, ATG4B Cysteine protease ATG4B is an enzyme that in huma ...

, GABARAPL1, GAST,

BCAR3 Breast cancer anti-estrogen resistance protein 3 is a protein that in humans is encoded by the ''BCAR3'' gene. Function Breast tumors are initially dependent on estrogens for growth and progression and can be inhibited by anti-estrogens such a ...

EPB41 Protein 4.1, also known as Beatty's Protein, is a protein associated with the cytoskeleton that in humans is encoded by the ''EPB41'' gene. Protein 4.1 is a major structural element of the erythrocyte membrane skeleton. It plays a key role in reg ...

TNFRSF1A Tumor necrosis factor receptor 1 (TNFR1), also known as tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) and CD120a, is a ubiquitous membrane receptor that binds tumor necrosis factor-alpha (TNFα). Function The protein encoded b ...

HLA-B HLA-B (major histocompatibility complex, class I, B) is a human gene that provides instructions for making a protein that plays a critical role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen (HLA) compl ...

NFKB2 Nuclear factor NF-kappa-B p100 subunit is a protein that in humans is encoded by the ''NFKB2'' gene. Function NF-κB has been detected in numerous cell types that express cytokines, chemokines, growth factors, cell adhesion molecules, and some ...

, MAP3K1,

IKBKE Inhibitor of nuclear factor kappa-B kinase subunit epsilon also known as I-kappa-B kinase epsilon or IKK-epsilon is an enzyme that in humans is encoded by the ''IKBKE'' gene. Interactions IKBKE has been shown to interact with TANK. Function ...

PRKAB1 5'-AMP-activated protein kinase subunit beta-1 is an enzyme that in humans is encoded by the ''PRKAB1'' gene. The protein encoded by this gene is a regulatory subunit of the AMP-activated protein kinase (AMPK). AMPK is a heterotrimer consisting o ...

RIPK3 Receptor-interacting serine/threonine-protein kinase 3 is an enzyme that is encoded by the ''RIPK3'' gene in humans. The product of this gene is a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases. It cont ...

CD74 HLA class II histocompatibility antigen gamma chain also known as HLA-DR antigens-associated invariant chain or CD74 (Cluster of Differentiation 74), is a protein that in humans is encoded by the ''CD74'' gene. The invariant chain (Abbreviated Ii ...

NR4A1 The nuclear receptor 4A1 (NR4A1 for "nuclear receptor subfamily 4 group A member 1") also known as Nur77, TR3, and NGFI-B is a protein that in humans is encoded by the ''NR4A1'' gene. Nuclear receptor 4A1 (NR4A1) is a member of the ''NR4A'' nucle ...

, cdsA, mtaD,

ATXN2L Ataxin-2-like protein was initially identified in 1996 and designated Ataxin-2 Related protein (A2RP) as the search for the gene causing SCA2 lead to the identification of 2 cDNA clones with high similarity to ATXN2 (Pulst et al, 1996). It was lat ...

, ABCF2, and

MAPK3 Mitogen-activated protein kinase 3, also known as p44MAPK and ERK1, is an enzyme that in humans is encoded by the ''MAPK3'' gene. Function The protein encoded by this gene is a member of the mitogen-activated protein kinase (MAP kinase) famil ...

References

External links