PPO resistance
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Protoporphyrinogen oxidase or protox 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 ''PPOX''
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 ...
. Protoporphyrinogen oxidase is responsible for the seventh step in biosynthesis of
protoporphyrin IX Protoporphyrin IX is an organic compound, classified as a porphyrin, that plays an important role in living organisms as a precursor to other critical compounds like heme (hemoglobin) and chlorophyll. It is a deeply colored solid that is not solu ...
. This porphyrin is the precursor to
hemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythroc ...
, the
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements ...
carrier in animals, and chlorophyll, the dye in plants. The enzyme catalyzes the
dehydrogenation In chemistry, dehydrogenation is a chemical reaction that involves the removal of hydrogen, usually from an organic molecule. It is the reverse of hydrogenation. Dehydrogenation is important, both as a useful reaction and a serious problem. A ...
(removal of
hydrogen Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-to ...
atoms) of protoporphyrinogen IX (the product of the sixth step in the production of heme) to form protoporphyrin IX. One additional enzyme must modify protoporphyrin IX before it becomes heme. Inhibition of this enzyme is a strategy used in certain
herbicide Herbicides (, ), also commonly known as weedkillers, are substances used to control undesired plants, also known as weeds.EPA. February 201Pesticides Industry. Sales and Usage 2006 and 2007: Market Estimates. Summary in press releasMain page f ...
s.


Gene

The PPOX gene is located on the long (q) arm of
chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non- sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which ...
at position 22, from
base pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both D ...
157,949,266 to base pair 157,954,082.


Function

This gene encodes the penultimate enzyme of heme biosynthesis, which catalyzes the 6-electron oxidation of protoporphyrinogen IX to form
protoporphyrin IX Protoporphyrin IX is an organic compound, classified as a porphyrin, that plays an important role in living organisms as a precursor to other critical compounds like heme (hemoglobin) and chlorophyll. It is a deeply colored solid that is not solu ...
. This protein is a
flavoprotein Flavoproteins are proteins that contain a nucleic acid derivative of riboflavin. Flavoproteins are involved in a wide array of biological processes, including removal of radicals contributing to oxidative stress, photosynthesis, and DNA repair. T ...
associated with the outer surface of the
inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. ...
.


Heme biosynthetic pathway

The following genes encode enzymes that catalyze the various steps in the heme
biosynthetic Biosynthesis is a multi-step, enzyme-Catalysis, catalyzed process where substrate (chemistry), substrates are converted into more complex Product (chemistry), products in living organisms. In biosynthesis, simple Chemical compound, compounds are mo ...
pathway: * ''
ALAD Aminolevulinic acid dehydratase (porphobilinogen synthase, or ALA dehydratase, or aminolevulinate dehydratase) is an enzyme () that in humans is encoded by the ''ALAD'' gene. Porphobilinogen synthase (or ALA dehydratase, or aminolevulinate de ...
'': aminolevulinate, delta-, dehydratase * ''
ALAS1 Delta-aminolevulinate synthase 1 also known as ALAS1 is a protein that in humans is encoded by the ''ALAS1'' gene. ALAS1 is an aminolevulinic acid synthase. Delta-aminolevulinate synthase catalyzes the condensation of glycine with succinyl-CoA t ...
'': aminolevulinate, delta-, synthase 1 * ''
ALAS2 Delta-aminolevulinate synthase 2 also known as ALAS2 is a protein that in humans is encoded by the ''ALAS2'' gene. ALAS2 is an aminolevulinic acid synthase. The product of this gene specifies an erythroid-specific mitochondrially located enzym ...
'': aminolevulinate, delta-, synthase 2 (sideroblastic/hypochromic anemia) * '' CPOX'': coproporphyrinogen oxidase * '' FECH'': ferrochelatase (protoporphyria) * '' HMBS'': hydroxymethylbilane synthase * ''PPOX'': protoporphyrinogen oxidase * ''
UROD Uroporphyrinogen III decarboxylase (uroporphyrinogen decarboxylase, or UROD) is an enzyme () that in humans is encoded by the ''UROD'' gene. Function Uroporphyrinogen III decarboxylase is a homodimeric enzyme () that catalyzes the fifth step ...
'': uroporphyrinogen decarboxylase * ''
UROS The Uru or Uros ( ure, Qhas Qut suñi) are an indigenous people of Bolivia. They live on an approximate and still growing 120 self-fashioned floating islands in Lake Titicaca near Puno. They form three main groups: the Uru-Chipaya, Uru-Murat ...
'': uroporphyrinogen III synthase (congenital erythropoietic porphyria)


Clinical significance

Variegate porphyria Variegate porphyria, also known by several other names, is an autosomal dominant porphyria that can have acute (severe but usually not long-lasting) symptoms along with symptoms that affect the skin. The disorder results from low levels of the en ...
is caused by mutations in the PPOX gene. More than 100 mutations that can cause variegate porphyria have been identified in the PPOX gene. One mutation, a substitution of the
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 ...
tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromatic ...
for
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
at position 59 (also written as Arg59Trp or R59W), is found in about 95 percent of South African families with variegate porphyria. Mutations in the PPOX gene reduce the activity of the enzyme made by the gene, allowing byproducts of heme production to build up in the body. This buildup, in combination with nongenetic factors (such as certain drugs,
alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...
and dieting), causes this type of porphyria.


Inhibitors as herbicides

Inhibition of protoporphyrinogen oxidase is a mechanism of action for several commercial herbicides including the nitrophenyl ethers
acifluorfen Acifluorfen is the ISO common name for an organic compound used as an herbicide. It acts by inhibiting the enzyme protoporphyrinogen oxidase which is necessary for chlorophyll synthesis. Soybeans naturally have a high tolerance to acifluorfen and ...
and
fomesafen Fomesafen is the ISO common name for an organic compound used as an herbicide. It acts by inhibiting the enzyme protoporphyrinogen oxidase which is necessary for chlorophyll synthesis. Soybeans naturally have a high tolerance to fomesafen, via ...
and the
pyrimidinedione Pyrimidinediones are a class of chemical compounds characterized by a pyrimidine ring substituted with two carbonyl groups. Examples include naturally occurring metabolites: drugs: * Fluorouracil * Idoxuridine * Primidone * Trifluridine and p ...
s
butafenacil Butafenacil is the ISO common name for an organic compound of the pyrimidinedione chemical class used as an herbicide. It acts by inhibiting the enzyme protoporphyrinogen oxidase to control broadleaf and some grass weeds in crops including cere ...
and
saflufenacil Saflufenacil is the ISO common name for an organic compound of the pyrimidinedione chemical class used as an herbicide. It acts by inhibiting the enzyme protoporphyrinogen oxidase to control broadleaf weeds in crops including soybeans and corn. ...
. The visible symptoms of treatment are
chlorosis In botany, chlorosis is a condition in which leaves produce insufficient chlorophyll. As chlorophyll is responsible for the green color of leaves, chlorotic leaves are pale, yellow, or yellow-white. The affected plant has little or no ability to ...
and
desiccation Desiccation () is the state of extreme dryness, or the process of extreme drying. A desiccant is a hygroscopic (attracts and holds water) substance that induces or sustains such a state in its local vicinity in a moderately sealed container. ...
. The damage is caused by an accumulation of protoporphyrin IX in the plant cells by inhibiting protox within the tetrapyrrole biosynthesis pathway. This is a potent
photosensitizer Photosensitizers produce a physicochemical change in a neighboring molecule by either donating an electron to the substrate or by abstracting a hydrogen atom from the substrate. At the end of this process, the photosensitizer eventually returns t ...
which activates oxygen, leading to
lipid peroxidation Lipid peroxidation is the chain of reactions of oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chai ...
. Both light and oxygen are required for this process to kill the plant.


See also

*
Porphyrin Porphyrins ( ) are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical com ...


References


Further reading

* * * * * * * * * * * * * * * * * * * * * *


External links


PDBe-KB
provides an overview of all the structure information available in the PDB for Human Protoporphyrinogen oxidase {{Portal bar, Biology, border=no EC 1.3.3