NADH dehydrogenase
biquinoneflavoprotein 1, mitochondrial (NDUFV1) is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
that in humans is encoded by the ''NDUFV1''
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 b ...
.
The NDUFV1 gene encodes the 51-kD subunit of
complex I
Respiratory complex I, (also known as NADH:ubiquinone oxidoreductase, Type I NADH dehydrogenase and mitochondrial complex I) is the first large protein complex of the respiratory chains of many organisms from bacteria to humans. It catalyzes the ...
(NADH:ubiquinone oxidoreductase) of the mitochondrial
respiratory chain
An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples thi ...
. Defects in complex I are a common cause of mitochondrial dysfunction. Mitochondrial complex I deficiency is linked to
myopathies
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 mean ...
, encephalomyopathies, and neurodegenerative disorders such as
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
and
Leigh syndrome
Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who fi ...
.
Structure
''NDUFV1'' is located on the
q arm
In genetics, a locus (plural loci) is a specific, fixed position on a chromosome where a particular gene or genetic marker is located. Each chromosome carries many genes, with each gene occupying a different position or locus; in humans, the total ...
of
chromosome 11
Chromosome 11 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome. Chromosome 11 spans about 135 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...
in position 13.2 and has 10
exons.
The ''NDUFV1'' gene produces a 50.8 kDa protein composed of 464
amino acid
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 a ...
s. NDUFV1, the protein encoded by this gene, is a member of the complex I 51 kDa subunit family. This subunit carries the
NADH
Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...
-binding site as well as
flavin mononucleotide
Flavin mononucleotide (FMN), or riboflavin-5′-phosphate, is a biomolecule produced from riboflavin (vitamin B2) by the enzyme riboflavin kinase and functions as the prosthetic group of various oxidoreductases, including NADH dehydrogenase, as we ...
(FMN)- and Fe-S-binding sites.
It also contains a
transit peptide
A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16-30 amino acids long) present at the N-ter ...
domain and is composed of 6 turns, 14
beta strands
Beta (, ; uppercase , lowercase , or cursive ; grc, βῆτα, bē̂ta or ell, βήτα, víta) is the second letter of the Greek alphabet. In the system of Greek numerals, it has a value of 2. In Modern Greek, it represents the voiced labio ...
, and 19
alpha helixes.
Function
Complex I
Respiratory complex I, (also known as NADH:ubiquinone oxidoreductase, Type I NADH dehydrogenase and mitochondrial complex I) is the first large protein complex of the respiratory chains of many organisms from bacteria to humans. It catalyzes the ...
is composed of 45 different subunits. NDUFV1 is a component of the flavoprotein-sulfur (FP) fragment of the enzyme. NDUFV1 is an
oxidoreductase
In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor. This group of enzymes usually u ...
and core subunit of complex I that is thought to be required for assembly and catalysis. It is a
peripheral membrane protein
Peripheral membrane proteins, or extrinsic membrane proteins, are membrane proteins that adhere only temporarily to the biological membrane with which they are associated. These proteins attach to integral membrane proteins, or penetrate the perip ...
located on the
matrix
Matrix most commonly refers to:
* ''The Matrix'' (franchise), an American media franchise
** ''The Matrix'', a 1999 science-fiction action film
** "The Matrix", a fictional setting, a virtual reality environment, within ''The Matrix'' (franchis ...
side of the
mitochondrion inner membrane.
Catalytic Activity
NADH +
ubiquinone
Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10.
It is a 1,4-benzoq ...
+ 5 H+(In) = NAD+ +
ubiquinol
A ubiquinol is an electron-rich (reduced) form of coenzyme Q (ubiquinone). The term most often refers to ubiquinol-10, with a 10-unit tail most commonly found in humans.
The natural ubiquinol form of coenzyme Q is 2,3-dimethoxy-5-methyl-6-poly ...
+ 4 H+(Out).
NADH + acceptor = NAD+ + reduced acceptor.
Clinical significance
Mutations in the ''NDUFV1'' gene are associated with Mitochondrial Complex I Deficiency, which is
autosomal recessive. This deficiency is the most common enzymatic defect of the
oxidative phosphorylation disorders. Mitochondrial complex I deficiency shows extreme
genetic heterogeneity Genetic heterogeneity occurs through the production of single or similar phenotypes through different genetic mechanisms. There are two types of genetic heterogeneity: allelic heterogeneity, which occurs when a similar phenotype is produced by diffe ...
and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious
genotype–
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological pr ...
correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible. However, the majority of cases are caused by mutations in nuclear-encoded genes. It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include
macrocephaly
Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to ...
with progressive
leukodystrophy
Leukodystrophies are a group of usually inherited disorders characterized by degeneration of the white matter in the brain. The word ''leukodystrophy'' comes from the Greek roots ''leuko'', "white", ''dys'', "abnormal" and ''troph'', "growth". Th ...
, nonspecific
encephalopathy
Encephalopathy (; from grc, ἐνκέφαλος "brain" + πάθος "suffering") means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but r ...
,
hypertrophic cardiomyopathy,
myopathy,
liver disease
Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.
Signs and symptoms
Some of the si ...
,
Leigh syndrome
Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who fi ...
,
Leber hereditary optic neuropathy, and some forms of
Parkinson disease Parkinson may refer to:
*Parkinson (surname)
* ''Parkinson'' (TV series), British chat show, presented by Sir Michael Parkinson
*Parkinson, Queensland, suburb of Brisbane, Australia
*The Parkinsons (fl. early 20th century), American father-and-son ...
. Clinical manifestations can include
lactic acidosis
Lactic acidosis is a medical condition characterized by a build-up of lactate (especially -lactate) in the body, with formation of an excessively low pH in the bloodstream. It is a form of metabolic acidosis, in which excessive acid accumulates d ...
,
cerebral degeneration,
ophthalmoplegia
Ophthalmoparesis refers to weakness (-paresis) or paralysis (-plegia) of one or more extraocular muscles which are responsible for eye movements. It is a physical finding in certain neurologic, ophthalmologic, and endocrine disease.
Internal ...
,
ataxia
Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
,
spasticity
Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles ...
, and
dystonia resulting from mutations in ''NDUFV1''.
Interactions
NDUFV1 has been shown to have 103 binary
protein-protein interactions including 97 co-complex interactions. NDUFV1 appears to interact with
EWSR1
RNA-binding protein EWS is a protein that in humans is encoded by the ''EWSR1'' gene on human chromosome 22, specifically 22q12.2. It is one of 3 proteins in the FET protein family. The q22.2 region of chromosome 22 encodes the N-terminal transact ...
,
CREB1
CAMP responsive element binding protein 1, also known as CREB-1, is a protein that in humans is encoded by the ''CREB1'' gene. This protein binds the cAMP response element, a DNA nucleotide sequence present in many viral and cellular promoters. ...
,
NCOR1
The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 (TRAC-1) is a protein that in humans is encoded by the ''NCOR1'' gene.
NCOR1 is a transcriptional coregulatory protein which c ...
, and
VDAC1.
References
Further reading
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{{Enzymes
Human proteins
EC 1.6.5