Smooth endoplasmic reticulum

The smooth endoplasmic reticulum (SER) has functions in several metabolic processes,
including synthesis of lipids and steroids, metabolism of carbohydrates, regulation of calcium
concentration, drug detoxification, attachment of receptors on cell membrane proteins, and
steroid metabolism.[7] It is connected to the nuclear envelope. Smooth endoplasmic reticulum is
found in a variety of cell types (both animal and plant) and it serves different functions in each.
The Smooth ER also contains the enzyme glucose-6-phosphatase which converts glucose-6-
phosphate to glucose, a step in gluconeogenesis. The SER consists of tubules and vesicles that
branch forming a network. In some cells there are dilated areas like the sacs of RER. The
network of SER allows increased surface area for the action or storage of key enzymes and the
products of these enzymes.
Sarcoplasmic reticulum
The sarcoplasmic reticulum (SR), from the Greek sarx, ("flesh"), is a special type of smooth ER
found in smooth and striated muscle. The only structural difference between this organelle and
the SER is the medley of proteins they have, both bound to their membranes and drifting within
the confines of their lumens. This fundamental difference is indicative of their functions: the
SER synthesizes molecules while the SR stores and pumps calcium ions. The SR contains large
stores of calcium, which it sequesters and then releases when the muscle cell is stimulated.[8] The
SR's release of calcium upon electrical stimulation of the cell plays a major role in excitation-
contraction coupling.
Functions
The endoplasmic reticulum serves many general functions, including the facilitation of protein
folding and the transport of synthesized proteins in sacs called cisternae.
Correct folding of newly-made proteins is made possible by several endoplasmic reticulum
chaperone proteins, including protein disulfide isomerase (PDI), ERp29, the Hsp70 family
member Grp78, calnexin, calreticulin, and the peptidylpropyl isomerase family. Only properly-
folded proteins are transported from the rough ER to the Golgi complex.
Transport of proteins
Secretory proteins, mostly glycoproteins, are moved across the endoplasmic reticulum
membrane. Proteins that are transported by the endoplasmic reticulum and from there throughout
the cell are marked with an address tag called a signal sequence. The N-terminus (one end) of a
polypeptide chain (i.e., a protein) contains a few amino acids that work as an address tag, which
are removed when the polypeptide reaches its destination. Proteins that are destined for places
outside the endoplasmic reticulum are packed into transport vesicles and moved along the
cytoskeleton toward their destination.
The endoplasmic reticulum is also part of a protein sorting pathway. It is, in essence, the
transportation system of the eukaryotic cell. The majority of endoplasmic reticulum resident
proteins are retained in the endoplasmic reticulum through a retention motif. This motif is
composed of four amino acids at the end of the protein sequence. The most common retention
sequence is KDEL (lys-asp-glu-leu). However, variation on KDEL does occur and other
sequences can also give rise to endoplasmic reticulum retention. It is not known if such variation
can lead to sub-endoplasmic reticulum localizations. There are three KDEL receptors in
mammalian cells, and they have a very high degree of sequence identity. The functional
differences between these receptors remain to be established.
Other functions
• Insertion of proteins into the endoplasmic reticulum membrane: Integral membrane
proteins are inserted into the endoplasmic reticulum membrane as they are being
synthesized (co-translational translocation). Insertion into the endoplasmic reticulum
membrane requires the correct topogenic signal sequences in the protein.
• Glycosylation: Glycosylation involves the attachment of oligosaccharides.
• Disulfide bond formation and rearrangement: Disulfide bonds stabilize the tertiary
and quaternary structure of many proteins.
• Drug Metabolism: The smooth ER is the site at which some drugs are modified by
microsomal enzymes which include the cytochrome P450 enzymes.
See also
• ERAD
• Protein targeting
• Secretory pathway
• Reticulons
References
1. ^ Porter KR, Claude A, Fullam EF (March 1945). "A study of tissue culture cells by
electron microscopy". J Exp Med. 81: 233–246. doi:10.1084/jem.81.3.233.
2. ^ Campbell, Neil A. (1996) Biology Fourth Edition. Benjamin/Cummings Publishing, pp.
120-121 ISBN 0-8053-1940-9
3. ^ Lodish, Harvey, et al. (2003) Molecular Cell Biology 5th Edition. W. H. Freeman, pp.
659-666 ISBN 0716743663
4. ^ Endoplasmic reticulum. (n.d.). McGraw-Hill Encyclopedia of Science and Technology.
Retrieved September 13, 2006, from Answers.com Web site:
http://www.answers.com/topic/endoplasmic-reticulum
5. ^ Levine T (September 2004). "Short-range intracellular trafficking of small molecules
across endoplasmic reticulum junctions". Trends Cell Biol. 14 (9): 483–90.
doi:10.1016/j.tcb.2004.07.017. PMID 15350976.
http://linkinghub.elsevier.com/retrieve/pii/S0962-8924(04)00196-5.
6. ^ Levine T, Loewen C (August 2006). "Inter-organelle membrane contact sites: through a
glass, darkly". Curr. Opin. Cell Biol. 18 (4): 371–8. doi:10.1016/j.ceb.2006.06.011.
PMID 16806880.
7. ^ Maxfield FR, Wüstner D (October 2002). "Intracellular cholesterol transport". J. Clin.
Invest. 110 (7): 891–8. doi:10.1172/JCI16500. PMID 12370264.
8. ^ Toyoshima C, Nakasako M, Nomura H, Ogawa H (2000). "Crystal structure of the
calcium pump of sarcoplasmic reticulum at 2.6 A resolution". Nature 405 (6787): 647–
55. doi:10.1038/35015017. PMID 10864315.
External links
• Lipid and protein composition of Endoplasmic reticulum in OPM database
 • Animations of the various cell functions referenced here

Drug metabolism
From Wikipedia, the free encyclopedia
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Drug metabolism is the metabolism of drugs, their biochemical modification or degradation,

usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug
metabolism often converts lipophilic chemical compounds into more readily excreted polar
products. Its rate is an important determinant of the duration and intensity of the pharmacological
action of drugs.
Drug metabolism can result in toxication or detoxication - the activation or deactivation of the
chemical. While both occur, the major metabolites of most drugs are detoxication products.
Drugs are almost all xenobiotics. Other commonly used organic chemicals are also xenobiotics,
and are metabolized by the same enzymes as drugs. This provides the opportunity for drug-drug
and drug-chemical interactions or reactions.

Contents
[hide]
• 1 Phase I vs. Phase II
• 2 Sites
• 3 Major enzymes and pathways
○ 3.1 Phase I
 3.1.1 Oxidation
 3.1.2 Reduction
 3.1.3 Hydrolysis
○ 3.2 Phase II
 3.2.1 Methylation
 3.2.2 Sulphation
 3.2.3 Acetylation
 3.2.4 Glucuronidation
• 4 Factors that affect Drug Metabolism
• 5 See also
• 6 References
• 7 External links

[edit] Phase I vs. Phase II

Phase I and Phase II reactions are biotransformations of chemicals that occur during drug
metabolism.
Phase I reactions usually precede Phase II, though not necessarily. During these reactions, polar
bodies are either introduced or unmasked, which results in (more) polar metabolites of the
original chemicals. In the case of pharmaceutical drugs, Phase I reactions can lead either to
activation or inactivation of the drug.
Phase I reactions (also termed nonsynthetic reactions) may occur by oxidation, reduction,
hydrolysis, cyclization, and decyclization reactions. Oxidation involves the enzymatic addition
of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver.
These oxidative reactions typically involve a cytochrome P450 monooxygenase (often
abbreviated CYP), NADPH and oxygen. The classes of pharmaceutical drugs that utilize this
method for their metabolism include phenothiazines, paracetamol, and steroids. If the
metabolites of phase I reactions are sufficiently polar, they may be readily excreted at this point.
However, many phase I products are not eliminated rapidly and undergo a subsequent reaction in
which an endogenous substrate combines with the newly incorporated functional group to form a
highly polar conjugate.
A common Phase I oxidation involves conversion of a C-H bond to a C-OH. This reaction
sometimes converts a pharmacologically inactive compound (a prodrug) to a pharmacologically
active one. By the same token, Phase I can turn a nontoxic molecule into a poisonous one
(toxification). A famous example is acetonitrile, CH3CN. Simple hydrolysis in the stomach
transforms acetonitrile into acetate and ammonia, which are comparatively innocuous. But Phase
I metabolism converts acetonitrile to HOCH2CN, which rapidly dissociates into formaldehyde
and hydrogen cyanide, both of which are toxic.
Phase I metabolism of drug candidates can be simulated in the laboratory using non-enzyme
catalysts.[1] This example of a biomimetic reaction tends to give a mixture of products that often
contains the Phase I metabolites, and Alpha Chimica's approach to preparing prospective drug
candidates makes use of this in vitro chemistry.
Phase II reactions — usually known as conjugation reactions (e.g., with glucuronic acid,
sulfonates (commonly known as sulfation) , glutathione or amino acids) — are usually
detoxication in nature, and involve the interactions of the polar functional groups of phase I
metabolites. Sites on drugs where conjugation reactions occur include carboxyl (-COOH),
hydroxyl (-OH), amino (NH2), and sulfhydryl (-SH) groups. Products of conjugation reactions
have increased molecular weight and are usually inactive unlike Phase I reactions which often
produce active metabolites.
[edit] Sites
Quantitatively, the smooth endoplasmic reticulum of the liver cell is the principal organ of drug
metabolism, although every biological tissue has some ability to metabolize drugs. Factors
responsible for the liver's contribution to drug metabolism include that it is a large organ, that it
is the first organ perfused by chemicals absorbed in the gut, and that there are very high
concentrations of most drug-metabolizing enzyme systems relative to other organs. If a drug is
taken into the GI tract, where it enters hepatic circulation through the portal vein, it becomes
well-metabolized and is said to show the first pass effect.
Other sites of drug metabolism include epithelial cells of the gastrointestinal tract, lungs,
kidneys, and the skin. These sites are usually responsible for localized toxicity reactions.
[edit] Major enzymes and pathways
Several major enzymes and pathways are involved in drug metabolism, and can be divided into
Phase I and Phase II reactions:
[edit] Phase I
[edit] Oxidation
• Cytochrome P450 monooxygenase system
• Flavin-containing monooxygenase system
• Alcohol dehydrogenase and aldehyde dehydrogenase
• Monoamine oxidase
• Co-oxidation by peroxidases
[edit] Reduction
• NADPH-cytochrome P450 reductase
• Reduced (ferrous) cytochrome P450
It should be noted that during reduction reactions, a chemical can enter futile cycling, in which it
gains a free-radical electron, then promptly loses it to oxygen (to form a superoxide anion).
[edit] Hydrolysis
• Esterases and amidases
• Epoxide hydrolase
[edit] Phase II
[edit] Methylation
• methyltransferase
[edit] Sulphation
• Glutathione S-transferases
• Sulfotransferases
[edit] Acetylation
• N-acetyltransferases
• Amino acid N-acyl transferases
[edit] Glucuronidation
• UDP-glucuronosyltransferases
○ Mercapturic acid biosynthesis

[edit] Factors that affect Drug Metabolism

The duration and intensity of pharmacological action of most lipophilic drugs are determined by
the rate they are metabolized to inactive products. The Cytochrome P450 monooxygenase
system is the most important pathway in this regard. In general, anything that increases the rate
of metabolism (e.g., enzyme induction) of a pharmacologically active metabolite will decrease
the duration and intensity of the drug action. The opposite is also true (e.g., enzyme inhibition).
Various physiological and pathological factors can also affect drug metabolism. Physiological
factors that can influence drug metabolism include age, individual variation (e.g.,
pharmacogenetics), enterohepatic circulation, nutrition, intestinal flora, or sex differences.
In general, drugs are metabolized more slowly in fetal, neonatal and elderly humans and animals
than in adults.
Genetic variation (polymorphism) accounts for some of the variability in the effect of drugs.
With N-acetyltransferases (involved in Phase II reactions), individual variation creates a group
of people who acetylate slowly (slow acetylators) and those who acetylate quickly, split roughly
50:50 in the population of Canada. This variation may have dramatic consequences, as the slow
acetylators are more prone to dose-dependent toxicity.
Cytochrome P450 monooxygenase system enzymes can also vary across individuals, with
deficiencies occurring in 1 - 30% of people, depending on their ethnic background.
Pathological factors can also influence drug metabolism, including liver, kidney, or heart
diseases.
In silico modelling and simulation methods allow drug metabolism to be predicted in virtual
patient populations prior to performing clinical studies in human subjects.[2] This can be used to
identify individuals most at risk from adverse reaction.
[edit] See also
• Drug design
• Xenobiotic metabolism
• Active metabolite
• Drug reaction testing
• SPORCalc, an example process for exploring drug metabolism databases[3]
• Simcyp Simulator
• Simulations Plus

[edit] References
1. ^ Bernardin Akagah; Anh Tuan Lormier; Alain Fournet; Bruno Figadere
(2008). "Oxidation of antiparasitic 2-substituted quinolines using
metalloporphyrin catalysts: scale-up of a biomimetic reaction for metabolite
production of drug candidates". Organic & Biomolecular Chemistry 6 (24):
4494–7. PMID 19039354.
2. ^ Amin Rostami-Hodjegan; Geoffrey Tucker (2007). "Simulation and
prediction of in vivo drug metabolism in human populations from in vitro
data". Nature Reviews Drug Discovery 6 (2): 140–8. doi:10.1038/nrd2173.
PMID 17268485.
3. ^ James Smith; Viktor Stein (2009). "SPORCalc: A development of a database
analysis that provides putative metabolic enzyme reactions for ligand-based
drug design". Computational Biology and Chemistry 33 (2): 149–159.
doi:10.1016/j.compbiolchem.2008.11.002. PMID 19157988.
• Basic and Clinical Pharmacology (9th Edition; Katzung): 1.4. Drug
Biotransformation
[edit] External links
• University of Minnesota Biocatalysis/Biodegradation Database
• Drug Metabolism Database

Smooth endoplasmic reticulum

The smooth endoplasmic reticulum has functions in several metabolic processes, including
synthesis of lipids, metabolism of carbohydrates and calcium concentration, drug detoxification,
and attachment of receptors on cell membrane proteins. It is connected to the nuclear envelope.
Smooth endoplasmic reticulum is found in a variety of cell types (both animal and plant) and it
serves different functions in each. The Smooth ER also contains the enzyme Glucose-6-
phosphatase which converts glucose-6-phosphate to glucose, a step in gluconeogenesis.The
Smooth ER consists of tubules and vesicles that branch forming a network. In some cells there
are dilated areas like the sacs of rough endoplasmic reticulum. The network of smooth
endoplasmic reticulum allows increased surface area for the action or storage of key enzymes
and the products of these enzymes. The smooth endoplasmic reticulum is known for its storage
of calcium irons in muscle cells.

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