Category Archives: Biochemistry

When timing matters

Biochemistry, Cell physiology, Circadian Clock, Drug, Translation

When you are an endocrinologist you know that hormones are released into the circulation in pulses and that melatonin is only produced in the dark, that glucocortoids concentrations in the blood are high during the night and low during the day, that many hormones have their rhythm. Every hormone has its time, as the prophet sayed.

However, what has not been known until now is that to the same extend more than 40 % of all genes are expressed in a circadian (day long) rhythm.  Zhang and colleagues measured in the mouse ( and the might be the only shortcoming of the study ) the gene expression with arrays to determine many gene simultaneously in every hour of the day and night. They found 43 % of all genes expressed in a circadian rhythm. They also determined noncoding RNAs  and found 1000 of them cycling.

There are consequences for medicine and therapy: The targets of the top most drugs are expressed all in (specific) rhythms: When a drug like aspirin for example is taken at the wrong time, it would be gone before the target is fully expressed. The scale of this problem seems tremendous. Any pharmaceutical company has to do its home work again. But on the other hand, therapy might become more reliable which would be a large improvement.

The circadian rhythm in the 12 organs analysed are quite different. It might take some time to get used to the thinking that genes in question are not stable during the day but change the level of expression. It will be interesting to follow the aftermath of that paper. The paper is open access and therefore free to everybody.

A must.

 

Who is my neighbor?

Biochemistry, Cell physiology, Protein folding

To form stable connections to your neighbors is  a way to make daily life predictable even if the relations are inimical. Looking at an amino acid in a three-dimensional structure is likewise to look for neighbors at the amino acid level. This problem of protein folding has occupied biochemists for quite some time. Even with the biggest supercomputers it could not sufficiently be simulated.

In a Perspective article in PNAS Englander and Mayne from the Univ. Pennsylvania present the problem and the new technology which has helped to solve at least one structure’s folding. They show what is possible now and what cannot be done. At the origin of the problem are small units of folding which the form or donot form extended structures. Deuterium/hydrogen exchange experiments and their fast time-line-records are what can give information about the ways protein fold. This is an actual picture what has been achieved in the field. It is more that one could expect from the outside, but not enough to solve the puzzle. It seems at least that a mechanism of protein folding has been found.

Worth reading!

How an ABC transporter gets rid of arsenic

Biochemistry, Cell physiology,

Not only from Agatha Christie’s books we know that arsenic is toxic. It is even a carcinogen and, most importantly, is contaminating the groundwater in a lot of countries. Removing arsenic from water and food is a tremendous task and will improve the health of many people.

Therefore a paper on an ABC transporter in rice which excludes arsenic from the grains is a welcome addition to the tasks involved. ABC transporter are evolutionary very old molecules which transports ligands across membranes with the help of ATP. Song and colleagues found out that the rice (Oryza sativa) the ABC transporter C1 (OrABCC1) lowers the arsenic content in the grain therefore the food is not contaminated in the way the water it is grown is. The molecule is also expressed in other parts of rice. When genetically engineered into wheat, it could transfer the resistance to arsenic. In rice, its expression is increased when arsenic gets higher. It is arsenic specific, since when knock-out the arsenic resistance was gone but not the cadmium resistance.

Immunologists will know ABC transporters involved in the transfer of degraded peptides into the ER to be loaded eventually into the histocompatibility class I molecules. Obviously, they can do much more.

Recommended!

“Sport ist Mord”

Biochemistry, Cell physiology, Endocrinology

Obviously there is no easy translation for this German proverb: No sports, no sports is what Churchill said. Sport’s a killer, sport is murder doesn’t have the rhyme the German version has. Nevertheless, the people who say so are totally wrong. Exercise was the base that the human race could go where we are now, a overweight race with many problems due to sitting most of the time in our desk chairs while exercise is beyond the horizon and reserved to leisure. It had been just the opposite: running and hunting was the professional occupation and sitting at the fire the leisure. How time changes!

I was lead to this excurs by a review in Cell: Integrative Biology of Exercise by Howard and colleagues from Melbourne (Australia), Rochester (Maine), and Stockholm (Sweden). They bring the different aspects of Exercise into an systematic overview and nail the “Major Signaling Pathways Involved in the Control of Skeletal Muscle Hypertrophy and Mitochondrial Biogenesis” down to one image. Exercise involves “Complex and Redundant Physiological Control” in CNS, muscles, heart, lung, in the metabolism and neuroendocrine systems. The pictures are straight forward and very instructive. 

Recommended!

Dechlorination — how it works

Biochemistry, Endocrine Disruptors, Structure determination

In Science this week there is a paper by Brommer et al. from Berlin and Jena, Germany, who reports the structure of the enzyme dehalogenase from
Sulfurospirillum multivorans in complex with trichlorethane and a pseudo-vitamine B12 providing the cobalt ion for electron transfer. A Perspectives article by E.A. Edwards further explains the findings: the pseudo-vitamine B12 is protected from the outside by the dehalogenase and a channel of open for the substrate and its analog.

The immune system in jawless fish

Biochemistry, Immunology, Structure determination

That sharks share the antibody structure with men is already known for quite some time. Whether other animals, earlier in evolution, have also antibodies and T cells like ourselves has been a open question. The answer is yes, but….

An article in PNAS from the Max-Planck-Institute for Immunobiology, Freiburg, Germany (with contributions from the Emory Univ. Atlanta, the Univ. of Maryland and from National Library of Medicine, NIH) reports in detail about one (of three) antigen receptors in lampreys. These jawless fishes (whether they belong to vertebrates is open to discussion) have a repertoire of different receptors, but unlike antibodies where the variable region is composed of variable and constant elements and linked by diversity and joining elements they are build of a variable number of leucin-rich repeats which form a structure which is reminescent of glycoprotein receptors with a very similar organization: Continue reading The immune system in jawless fish →

Implantation revisited

Biochemistry, Endocrinology, Nuclear receptors, ,

Successful fertilization is only one half of the coin, implantation is the other half that is necessary that pregnancy can begin. As it is extremely difficult to observe normal human implantation not only for experimental, but for ethical reasons, too, the mouse is for several reasons the model of choice: implantation to occur at the blastocyst stage, only a narrow window for reception, decidualization of the stroma, invasion of the embryo into this stromal bed and a common hemochorial placentation.

In an excellent review in Molecular Endocrinology, Pawar, Hantak and Bagchi have summarized the actual knowledge about mouse implantation biology: crosstalk of estrogens and progesterons for proliferation and differentiation, estrogen and progesteron receptors at the start of signal cascades, paracrine factors as LIF, IHH, STATs, FGFs and EGF, the role of the stroma and the epithel. How the (experimental) lack of some of these proteins leads to infertility is convincingly described. It has not been a great surprise that they offer a explanation for endometriosis the disease where there is aberrant decidualisation in the peritoneum of women patients.

A must for gynaecologists!

A Structure for NO Synthase

Biochemistry, Immunology, Structure determination,

The NO synthases structures have been elusive so far. As these are fairly complex structures with different functional domains this is not very surprising. The role of these molecules in signal transduction is established and errors therein might lead to hypertension, erectile dysfunction, neurodegeneration, stroke or heart disease.

A PNAS paper this week has solved all the three structures of eNOS, iNOS, and nNOS. They used a high through put Electron microscopy single particle method to obtain the many different conformation in which these enzyme occurs. They have also solved the role of calmodulin in the enzymatic reaction and shown why the binding of calmodulin is a time limiting step (for two of the enzymes). Given the complexity of the molecular structures shown and the different confirmation obtained this is some nice piece of work: from the structure to the function. Beautifully done!

A StAR is everywhere!

Biochemistry, Endocrinology, Translation,

Steriod acute regulator protein (StAR) is the protein involved in the time-limiting step of stereogenesis since one molecule StAR must be produced to transport one molecule cholesterol  from the cell membrane to the mitochondrium. There, the side-chain cleavage enzyme converts the cholesterol to pregnenolone to begin the steroid synthesis for androgens and estrogens, mineralocorticoids and cortisols. StAR is therefore an important molecule for the Endocrinologist. Whereever StAR is expressed, steroids are supposed to be made. Its characteristic structure – a pocket to acquire just one molecule of cholesterol – has been crystallized and determined by X-ray spectrometry. What is much less known that it has homologues throughout the animal kingdom, even other taxa share the structure which is thus fairly old and that is used not only for cholesterol, but for numerous lipids, too.

Strange enough, a molecule which is at the beginning of a specialized reaction chain such as steroidogenesis is widely used. Sometimes the introduction to an article is an eye-opener: In Current Biology the paper by Schrick shows just such a case. They are concerned with StAR homologues in the plant Arabidopsis and their role as transcription factors. Maybe not so interesting to the general audience, but the introduction resumes the role of StAR and StAR-like proteins fairly well. Recommended.

The Proteasome adaptive response

Biochemistry, Cell physiology, ,

While you are most probably familiar with proteasomes (otherwise it is barrel-like structure with heptameric symmetry of four ring, holes at both end through which ubiquitin targets proteins to be digested during which process it produces peptides of seven to nine amino acids which are either digested or loaded into the peptide pockets of histocompatibility proteins) you would not have thought about how proteasomes themselves are regulated.  A free article in Molecular Cell (dx.doi.org/10.1016/j.molcel.2014.06.017) demonstrates that a protein Adc17 is induced in stress and helps to maintain adequate numbers of proteasomes. A nice piece of work!