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All-trans-retinal being converted back to 11-cis-retinal or vitamin A

All-trans-retinal being converted back to 11-cis-retinal or vitamin A



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There are two pathways all-trans-retinal can take after detaching from the scotopsin: (1) it can convert back to 11-cis-retinal, or (2) it can convert to all-trans-retinol (form of vitamin A), which then converts to 11-cis-retinol and then 11-cis-retinal. My question is what factors determine which pathway will occur?

The first sounds like it doesn't involve vitamin A at all and just recycles the retinal. Hence it wouldn't be affected by any vitamin A deficiency, yet we know vitamin A deficiency affects the stock of retinal in the eye. Yet I don't see any disadvantages in simply recycling our retinal; why would we go through the process of converting it to vitamin A and then back to 11-cis-retinal?


Short answer
A complex visual cycle in vertebrates involving vitamin A is useful for storage, re-distribution of retinoids to both rods and cones, to improve photosensitivity and reduce noise in the visual system.

Background
The visual cycle in mammalian rods is depicted in Fig. 1.


Fig. 1. Visual rod cycle. Source: Palczewski (2010)

11-cis-retinal isomerizes to all-trans retinal by absorption of a photon. Your notion that this pathway can involve direct re-isomerization back to 11-cis-retinal is only true for invertebrates. They simply absorb another photon to back-isomerize all-trans to 11-cis (Saari, 2012).

In vertebrates, however, this bi-stable configuration is replaced by a complex visual cycle (or retinoid cycle, Fig. 1). The reason is that the bi-stable invertebrate system is less sensitive, as photons used for regeneration cannot be used to initiate phototransduction. Moreover, the invertebrate system is more prone to noise, as photons can both start the phototransduction or recycle all-trans retinal (Saari, 2012).

In vertebrates it is thought that the visual cycle only emerged after appearance of the cone system (Saari, 2012). Notably, the visual cycle depends on the retinal pigment epithelum (RPE), as shown if Fig.2.


Fig. 2. Rod and cone visual cycle. Source: Saari (2012)

Fig. 2 shows that vitamin A (all-trans-retinol) is present in the RPE. RPE cells are able to store vitamin A by converting it to fatty acids and store it in oil droplets. Moreover, RPE cells can funnel this stored vitamin A to both rods and cones, another reason why the complex visual cycle and vitamin A conversion makes sense (Palczewski, 2010)

References
- Palczewski Trends Pharmacol Sci (2010); 31(6): 284-95
- Saari, Annu Rev Nutr (2012); 32: 125-45


11-Cis-Retinal

The unique attributes of the 11-cis-retinal that serves as the skeleton for all visual pigments are summarized in Figure 2 . The C20 11-cis-retinal, biosynthesized from the C40 β-carotene, is the basic structure of all visual pigments. The β-carotene produces C20 vitamin A (all-trans retinol), the precursor of retinal. However, since humans cannot biosynthesize carotenoids, we have to depend on exogenous sources for vision. The visual chromophore of salmons is 11-cis-retinal in fresh water but during their migratory period in the ocean, the becomes 3,4-dehydro-11-cis-retinal to induce a red shift in the vision more suited for the ocean where there is less light. The chromophore of the tadpole is also 3,4-dehydro-11-cis-retinal, which again becomes 11-cis-retinal in the frog. Squids have an additional 4-α-hydroxyl group [1] while insects have 3β-hydroxy-11-cis-retinal [2] , the chromophore possibly responsible for their UV sensitivity.

Figure 2 . Attributes of 11-cis-retinal as the visual chromophore


Photochemical events in vision involve the protein opsin and the cis/trans isomers of retinal. The cis-retinal fits into a receptor site of opsin. Upon absorption of a photon of light in the visible range, cis-retinal can isomerize to all-trans-retinal. In the cis-retinal, the hydrogens (light gray in the molecular model on the left) are on the same side of the double bond (yellow in the molecular model).

In the trans-retinal, the hydrogens are on opposite sides of the double bond. In fact, all of the double bonds are in the trans-configuration in this isomer: the hydrogens, or hydrogen and -CH3, are always on opposite sides of the double bonds (hence, the name "all-trans-retinal").

Note how the shape of the molecule changes as a result of this isomerization. The molecule changes from an overall bent structure to one that is more or less linear. All of this is the result of trigonal planar bonding (120 o bond angles) about the double bonds.

This photochemical reaction is best understood in terms of molecular orbitals, orbital energy, and electron excitation. In cis-retinal, absorption of a photon promotes a p electron in the pi bond to a higher-energy orbital. This excitation "breaks" the pi component of the double bond and is temporarily converted into a single bond. This means the molecule can now rotate around this single bond, which it does by swiveling through 180 o .

The double bond then reforms and locks the molecule back into position in a trans configuration of the all-trans-retinal. This isomerization occurs in a few picoseconds (10-12 s) or less. Energy from light is crucial for this isomerization process: absorption of a photon leads to breaking the double bond and consequent isomerization about half the time (in the dark is almost never happens.


Results

Inhibition of rod CNG channels by the retinoids was studied in inside-out patches excised from Xenopus oocytes expressing cloned homomultimeric CNGA1 channels. Fig. 1A shows families of macroscopic cGMP-activated currents recorded from a multichannel patch at several voltages. Addition of all-trans-retinal to the solution bathing the intracellular surface of the patch reduced the current in a dose-dependent manner at all voltages. Currents were recorded with saturating (2 mM) cGMP, and were monitored for several minutes after each addition of retinoid to ensure that the inhibition had reached steady-state. This length of time may have been required for the retinoids to insert into the membrane. Similar inhibition was seen with heteromeric (CNGA1/CNGB1) rod channels (data not shown). We were only able to achieve approximately 60% recovery of the current on washout (data not shown), presumably because it is difficult to remove the retinoids from the membrane. Fig. 1B presents an average dose-response relation for inhibition by all-trans-retinal for 5 patches, with all currents recorded at +100 mV in the presence of 2 mM cGMP. The IC50 for inhibition of the rod channel by all-trans-retinal at saturating cGMP was 0.35 μM.

In the presence of a saturating (2 mM) concentration of cGMP, rod channels are inhibited by all-trans-retinal. Data were measured from multichannel, inside-out patches of homomultimeric (CNGA1 only) rod channels. The families of cGMP-activated currents were recorded in response to voltage jumps ranging from −100 to +100 mV in steps of 50 mV, from a holding potential of 0 mV. Currents measured in the absence of cGMP were subtracted from all traces. (A) Current families demonstrating inhibition at saturating cGMP: control, 0.4 μM all-trans-retinal (40% inhibition), and 1.4 μM all-trans-retinal (87% inhibition). (B) Dose-response relation for inhibition by all-trans-retinal in saturating cGMP. Steady-state, cGMP-activated currents were measured at +100 mV from several patches at increasing concentrations of all-trans-retinal added to the solution bathing the “inside” surface of the patch. Averaged data were fit with the Hill equation, IN/INMAX = [all-trans-retinal] n /(IC50 n + [all-trans-retinal] n ), where IN is percent inhibition, INMAX is maximal inhibition, IC50 is the concentration of all-trans-retinal required to achieve half maximal inhibition, and n is the Hill coefficient. Data points are averaged values from 5 patches, and plotted with SD (error bars). INMAX = 100% IC50 = 0.35 μM and n = 1.5.

The rod CNG channel was also inhibited by 11-cis-retinal and by all-trans-retinol, although these retinoids demonstrated higher IC50's than that for all-trans-retinal. Fig. 2 shows dose-response relations for these two retinoids, measured at +100 mV. The IC50's were 0.88 μM for 11-cis-retinal and 0.99 μM for all-trans-retinol. All-trans-retinal was used for the remainder of the experiments described here because of its somewhat higher apparent affinity and its putative role in the bleaching response in rods (see Discussion).

Rod channels are inhibited by other retinoids less potently than by all-trans-retinal. (A) Dose–response relation for inhibition by 11-cis-retinal in saturating cGMP. Points are mean values from 2 to 4 patches along with SD (error bars). INMAX = 100% IC50 = 0.88 μM and n = 1.36. (B) Dose-response relation for inhibition by all-trans-retinol in saturating cGMP. Points are mean values from 2 to 4 patches along with SD (error bars). INMAX = 100% IC50 = 0.99 μM and n = 1.77.

The rod channel was much more sensitive to all-trans-retinal at low cGMP concentrations that are much closer to the levels (a few micromolar) expected in vivo (reviewed in ref. 29). Fig. 3 presents data like those in Fig. 1, except that the concentration of cGMP was only 15 μM, giving currents that were only about 8% of those obtained with saturating (2 mM) cGMP. The IC50 for inhibition by all-trans-retinal at this lower cGMP concentration was 35 nM, or only a tenth of that at saturating cGMP. Thus, all-trans-retinal appears to be a more effective inhibitor at low cGMP concentrations, either because it inhibits closed channels more effectively than open channels, or because it prefers unliganded channels.

Inhibition of rod channels by all-trans-retinal is more pronounced at low concentrations of cGMP. Recordings shown in A were made as those shown in Fig. 1, except that the bath concentration of cGMP was far below saturating, eliciting only ≈8% of the maximal current evoked by a saturating (2 mM) cGMP concentration. (A) Current families demonstrating inhibition at low (15 μM) cGMP: control, 40 nM all-trans-retinal (62% inhibition), and 140 nM all-trans-retinal (99% inhibition). (B) Dose–response relation for inhibition by all-trans-retinal in low cGMP. Measurements were made in a manner similar to those described in Fig. 1. Data were fit with the Hill equation as in Fig. 1. Data points with error bars (SD) are averaged values from 2 patches other points are from a single patch. Experiments with intermediate subsaturating cGMP concentrations yielded intermediate IC50s for inhibition by all-trans-retinal. INMAX = 100% IC50 = 35 nM and n = 1.5.

The notion that all-trans-retinal is a closed-state inhibitor is supported by results with the olfactory CNG channel. At saturating cGMP, when both rod and olfactory channels should be fully liganded, the olfactory channel has a greater open probability because of a lower free energy for opening (37). This phenomenon has been used to explain the fact that the olfactory channel is only partially inhibited by diacylglycerol (38) thus, the fully liganded olfactory channel is thought to open some of the time in the presence of such inhibitors, whereas the rod channel cannot. In other words, a more favorable energy of the opening transition makes closed-state inhibitors less effective. Fig. 4 demonstrates that at saturating (100 μM) cGMP the olfactory channel is also only slightly (10.7%) inhibited by all-trans-retinal. However, at low cGMP, when most of the channels would be closed, all-trans-retinal gives almost full (91.3%) inhibition.

Inhibition of the olfactory channel suggests that all-trans-retinal is a closed-state inhibitor. Steady-state currents were measured from patches of homomultimeric (CNGA2 only) olfactory channels at +100 mV. Data obtained at saturating cGMP (open circles) are the average of 2–4 patches with SD (error bars) and were fit with the Hill equation with the following parameters: INMAX = 10.7% IC50 = 0.27 μM and n = 2.90. Data obtained at low cGMP (filled triangles) are from a single patch and were fit with the Hill equation with INMAX = 91.3% IC50 = 0.12 μM and n = 2.47. These data are consistent with those from other experiments of this type with different subsaturating cGMP concentrations. The open triangle represents the recovery of much of the cGMP-activated current following the experiment at low cGMP through the addition of a saturating amount of cGMP. This finding demonstrates a reversibility of the inhibition without removal of the retinoid.

These olfactory channel data also provide evidence that all-trans-retinal actually affects channel gating, rather than just acting as a pore blocker that prefers closed channels. If all-trans-retinal were a closed-pore blocker, it would have at least some affinity for the open pore as well, so that the weak (10.7%) inhibition at saturating [cGMP] could be increased to 100% by raising the concentration of all-trans-retinal until all channels were blocked. If, on the other hand, all-trans-retinal inhibits channel opening, then the low fractional inhibition at saturating cGMP would reflect the favorable free energy of opening for the olfactory channel, allowing opening even in the presence of retinal. Thus, raising the concentration of all-trans-retinal would not give an additional reduction in current because the fractional inhibition would be limited by the gating equilibrium. Our results suggest that all-trans-retinal inhibits channel opening, rather than simply blocking the pore, because inhibition of the olfactory channel remains constant at 10.7% as the concentration of all-trans-retinal is raised to many times the IC50.

Single-channel recordings from the rod CNG channel suggest that all-trans-retinal induces a long-lived closed state (or states), effectively shutting down the channel for several seconds at a time. This inhibition is much more striking than that seen with most other inhibitors, such as tetracaine (39) and diacylglycerol (38). Fig. 5 shows that application of 0.4 μM all-trans-retinal to a patch containing two active channels in saturating [cGMP] reduced the open probability to such an extent that only one channel seemed to be active throughout many seconds of recording. This remaining channel activity demonstrated the same unitary current (i) and open probability (PO) as that measured before addition of all-trans-retinal. Raising the all-trans-retinal concentration to 1 μM completely shut down all channel activity for the duration of these recordings. Similar results were seen with six other patches containing 2–8 channels each. Two lines of evidence suggest that the extremely low channel open probability did not reflect damage to the channel protein or to the lipid bilayer by all-trans-retinal. First, in longer recordings, reopenings of the rod channel were occasionally seen. Second, after shutting down all of the olfactory channels in a multichannel patch in the presence of low cGMP, application of saturating cGMP reopened enough channels to give the same low maximal inhibition (10.7%) seen with inhibition of other patches at saturating cGMP (Fig. 4).

Single-channel analysis reveals a dramatic decrease in open probability by all-trans-retinal. Raw current traces in AD were recorded from a single inside-out patch containing 2 homomultimeric rod channels at a holding potential of +80 mV. Sampling rate was 25 kHz after filtering at 5 kHz. The line labeled c represents the zero-current level when both channels were closed. The upper two lines represent the current when one or both channels were open as determined from the fits to the histograms. Patches were bathed in the low divalent sodium solution (see Experimental Procedures) without cGMP (A), with saturating cGMP (B), and with two different all-trans-retinal concentrations at saturating cGMP as designated (C and D). Each amplitude histogram on the right was constructed from four 2.2-s traces of continuous recording. The application of 0.4 μM all-trans-retinal markedly decreases channel open probability, so that there are no simultaneous openings of two channels for the duration of this recording. There is no channel activity during the recording obtained in 1 μM all-trans-retinal. Histograms in A and D were fit with a Gaussian distribution. The histogram in B was fit by a sum of two Gaussian functions constrained so that the opening of the channels is described by a binomial distribution with the number of open channels n = 2 open probability PO = 0.97 single-channel current i = 2.49 pA and standard deviation σ = 0.60 pA. The histogram in C was fit by similar distributions, with n = 1 PO = 0.96 i = 2.50 pA and σ = 0.48 pA.


Rhodopsin Retinal Visual Cycle, and Excitation of the Rods - Photochemistry of Eye Vision

Rhodopsin and Its Decomposition by Light Energy. The outersegment of the rod that projects into the pigment layer of the retina has a concentration of about 40 per cent of the light-sensitive pigment called rhodopsin, or visual purple. This substance is a combination of theprotein scotopsin and the carotenoid pigment retinal (also called “retinene”). Furthermore, the retinal is a particular type called 11-cis retinal. This cis form of retinal is important because only this form can bind with scotopsin to synthesize rhodopsin.

When light energy is absorbed by rhodopsin, the rhodopsin begins to decompose within a very small fraction of a second, as shown at the top of Figure 50–5. The cause of this is photoactivation of electrons in the retinal portion of the rhodopsin, which leads to instantaneous change of the cis form of retinal into an all-trans form that still has the same chemical structure as the cis form but has a different physical structure— a straight molecule rather than an angulated molecule. Because the three-dimensional orientation of the reactive sites of the all-trans retinal no longer fits with the orientation of the reactive sites on the protein scotopsin, the all-transretinal begins to pullaway from the scotopsin. The immediate product is bathorhodopsin, which is a partially split combinationof the all-trans retinal and scotopsin. Bathorhodopsin


is extremely unstable and decays in nanoseconds to lumirhodopsin. This then decays in microsecondsto metarhodopsin I, then in about a millisecond to metarhodopsin II, and finally, much more slowly (inseconds), into the completely split products scotopsin and all-trans retinal.

It is the metarhodopsin II, also called activatedrhodopsin, that excites electrical changes in the rods,and the rods then transmit the visual image into the central nervous system in the form of optic nerve action potential, as we discuss later.

Re-formation of Rhodopsin. The first stage in re-formationof rhodopsin, as shown in Figure 50–5, is to reconvert the all-trans retinal into 11-cis retinal. This process requires metabolic energy and is catalyzed by the enzyme retinal isomerase. Once the 11-cis retinal is formed, it automatically recombines with the scotopsin to re-form rhodopsin, which then remains stable until its decomposition is again triggered by absorption of light energy.

Role of Vitamin A for Formation of Rhodopsin. Note inFigure 50–5 that there is a second chemical route by which all-trans retinal can be converted into 11-cis retinal.This is by conversion of the all-trans retinal first into all-trans retinol, which is one form of vitamin A. Then the all-trans retinol is converted into 11-cis retinol under the influence of the enzyme isomerase. Finally, the 11-cis retinol is converted into 11-cis retinal, which combines with scotopsin to form new rhodopsin.

Vitamin A is present both in the cytoplasm of the rods and in the pigment layer of the retina. Therefore, vitamin A is normally always available to form new retinal when needed. Conversely, when there is excess retinal in the retina, it is converted back into vitamin A, thus reducing the amount of light-sensitive pigment in the retina. We shall see later that this interconver-sion between retinal and vitamin A is especially impor-tant in long-term adaptation of the retina to different light intensities.

Night Blindness. Night blindness occurs in any personwith severe vitamin A deficiency. The simple reason for this is that without vitamin A, the amounts of retinal and rhodopsin that can be formed are severely depressed. This condition is called night blindnessbecause the amount of light available at night is too little to permit adequate vision in vitamin A–deficient persons.

For night blindness to occur, a person usually must remain on a vitamin A–deficient diet for months, because large quantities of vitamin A are normally stored in the liver and can be made available to the eyes. Once night blindness develops, it can sometimes be reversed in less than 1 hour by intravenous injection of vitamin A.

Excitation of the Rod When Rhodopsin Is Activated by Light

The Rod Receptor Potential Is Hyperpolarizing, Not Depolariz-ing. When the rod is exposed to light, the resulting receptor potential is different from the receptor poten-tials in almost all other sensory receptors. That is, exci-tation of the rod causes increased negativity of the intrarod membrane potential, which is a state of hyper-polarization, meaning that there is more negativitythan normal inside the rod membrane. This is exactly opposite to the decreased negativity (the process of “depolarization”) that occurs in almost all other sensory receptors.

But how does activation of rhodopsin cause hyper-polarization? The answer is that when rhodopsindecomposes, it decreases the rod membrane conduc-tance for sodium ions in the outer segment of the rod.

This causes hyperpolarization of the entire rod mem-brane in the following way.

Figure 50–6 shows movement of sodium ions in a complete electrical circuit through the inner and outer segments of the rod. The inner segment continually pumps sodium from inside the rod to the outside, thereby creating a negative potential on the inside of the entire cell. However, the outer segment of the rod, where the photoreceptor discs are located, is entirely different here, the rod membrane, in the dark state, is very leaky to sodium ions. Therefore, positively charged sodium ions continually leak back to the inside of the rod and thereby neutralize much of the negativity on the inside of the entire cell. Thus, undernormal dark conditions, when the rod is not excited, there is reduced electronegativity inside the membraneof the rod, measuring about –40 millivolts rather than the usual –70 to –80 millivolts found in most sensory receptors.


Then, when the rhodopsin in the outer segment of the rod is exposed to light, the rhodopsin begins to decompose, and this decreasesthe outer segment membrane conductance of sodium to the interior of the rod, even though sodium ions continue to be pumped outward through the membrane of the inner segment. Thus, more sodium ions now leave the rod than leak back in. Because they are positive ions, their loss from inside the rod creates increased negativity inside the membrane, and the greater the amount of light energy striking the rod, the greater the elec-tronegativity becomes—that is, the greater is the degree of hyperpolarization. At maximum light inten-sity, the membrane potential approaches –70 to –80 millivolts, which is near the equilibrium potential for potassium ions across the membrane.

Duration of the Receptor Potential, and Logarithmic Relation of the Receptor Potential to Light Intensity. When a sudden pulse of light strikes the retina, the transient hyperpolarization that occurs in the rods— that is, the receptor potential that occurs—reaches a peak in about 0.3 second and lasts for more than a second. In cones, the change occurs four times as fast as in the rods. A visual image impinged on the rods of the retina for only one millionth of a second can sometimes cause the sensation of seeing the image for longer than a second.

Another characteristic of the receptor potential is that it is approximately proportional to the logarithm of the light intensity. This is exceedingly important, because it allows the eye to discriminate light intensi-ties through a range many thousand times as great as would be possible otherwise.

Mechanism by Which Rhodopsin Decomposition Decreases Membrane Sodium Conductance—TheExcitation “Cascade.” Under optimal conditions, a single photon of light, the smallest possible quantal unit of light energy, can cause a measurable receptor potential in a rod of about 1 millivolt. Only 30 photons of light will cause half saturation of the rod. How can such a small amount of light cause such great excitation? The answer is that the photoreceptors have an extremely sensitive chemical cascade that amplifies the stimulatory effects about a millionfold, as follows:

1.The photon activates an electron in the 11-cis retinal portion of the rhodopsin this leads to the formation of metarhodopsin II,which is the active form of rhodopsin, as already discussed and shown in Figure 50–5.

2.The activated rhodopsin functions as an enzyme to activate many molecules of transducin, a protein present in an inactive form in the membranes of the discs and cell membrane of the rod.

3.The activated transducin activates many more molecules of phosphodiesterase.

4.Activated phosphodiesterase is another enzymeit immediately hydrolyzes many molecules of cyclic guanosine monophosphate (cGMP), thusdestroying it. Before being destroyed, the cGMP had been bound with the sodium channel protein of the rod’s outer membrane in a way that “splints” it in the open state. But in light, when phosphodiesterase hydrolyzes the cGMP, this removes the splinting and allows the sodium channels to close. Several hundred channels close for each originally activated molecule of rhodopsin. Because the sodium flux through each of these channels has been extremely rapid, flow of more than a million sodium ions is blocked by the channel closure before the channel opens again. This diminution of sodium ion flow is what excites the rod, as already discussed.

5.Within about a second, another enzyme, rhodopsin kinase, which is always present inthe rod, inactivates the activated rhodopsin (the metarhodopsin II), and the entire cascade reverses back to the normal state with open sodium channels.

Thus, the rods have developed an important chemi-cal cascade that amplifies the effect of a single photon of light to cause movement of millions of sodium ions. This explains the extreme sensitivity of the rods under dark conditions.

The cones are about 30 to 300 times less sensitive than the rods, but even this allows color vision at any intensity of light greater than extremely dim twilight.

Photochemistry of Color Vision by the Cones

It was pointed out at the outset of this discussion that the photochemicals in the cones have almost exactly the same chemical composition as that of rhodopsin in the rods. The only difference is that the protein por-tions, or the opsins—called photopsins in the cones— are slightly different from the scotopsin of the rods. The retinal portion of all the visual pigments is exactly the same in the cones as in the rods. The color-sensitive pigments of the cones, therefore, are combi-nations of retinal and photopsins.

In the discussion of color vision later, it will become evident that only one of three types of color pigments is present in each of the different cones, thus making the cones selectively sensitive to different colors: blue, green, or red. These color pigments are called, respectively, blue-sensitive pigment, green-sensitive pigment, and red-sensitive pigment. Theabsorption characteristics of the pigments in the three types of cones show peak absorbencies at light wave-lengths of 445, 535, and 570 nanometers, respectively.

These are also the wavelengths for peak light sensitiv-ity for each type of cone, which begins to explain how the retina differentiates the colors. The approximate absorption curves for these three pigments are shown in Figure 50–7. Also shown is the absorption curve for the rhodopsin of the rods, with a peak at 505 nanometers.


Abstract

Rhodopsin is the photosensitive pigment in the rod photoreceptor cell. Upon absorption of a photon, the covalently bound 11-cis-retinal isomerizes to the all-trans form, enabling rhodopsin to activate transducin, its G protein. All-trans-retinal is then released from the protein and reduced to all-trans-retinol. It is subsequently transported to the retinal pigment epithelium where it is converted to 11-cis-retinol and oxidized to 11-cis-retinal before it is transported back to the photoreceptor to regenerate rhodopsin and complete the visual cycle. In this study, we have measured the effects of all-trans- and 11-cis-retinals and -retinols on the opsin’s ability to activate transducin to ascertain their potentials for activating the signaling cascade. Only 11-cis-retinal acts as an inverse agonist to the opsin. All-trans-retinal, all-trans-retinol, and 11-cis-retinol are all agonists with all-trans-retinal being the most potent agonist and all-trans-retinol being the least potent. Taken as a whole, our study is consistent with the hypothesis that the steps in the visual cycle are optimized such that the rod can serve as a highly sensitive dim light receptor. All-trans-retinal is immediately reduced in the photoreceptor to prevent back reactions and to weaken its effectiveness as an agonist before it is transported out of the cell oxidation of 11-cis-retinol occurs in the retinal pigment epithelium and not the rod photoreceptor cell because 11-cis-retinol can act as an agonist and activate the signaling cascade if it were to bind an opsin, effectively adapting the cell to light.


Newly discovered chemical reaction in eye may improve vision

A light-sensing pigment found in everything from bacteria to vertebrates can be biochemically manipulated to reset itself, an important therapeutic advantage, according to new research out of Case Western Reserve University School of Medicine. In a study just released from the Proceedings of the National Academy of Sciences, researchers successfully used a modified form of vitamin A, called locked retinal, to induce the recycling mechanism and engage proteins central to human vision. The targeted proteins include light-sensing rhodopsin, which belongs to a family of proteins -- G protein-coupled receptors, or GPCRs -- that sit in cell membranes and transmit external cellular cues into internal cell signaling pathways. The discovery opens a new therapeutic opportunity for modified retinals that help improve vision, and offers a major improvement over current therapeutics designed to perturb cell signaling in the eye.

"Our study demonstrates a complete transition from a one-way activation of a GPCR into a self-renewing, recycling activation mechanism by the mere addition of a cyclohexyl chemical group to the retinal. These findings exemplify the possibility of reprogramming GPCRs into self-renewing machines that can be controlled by external cues. This biochemically induced function will be helpful in treating people with vision impairment, and opens up several avenues for more efficient GPCR-based therapeutics," said Sahil Gulati, first author of the study and graduate student in the department of pharmacology at Case Western Reserve University School of Medicine. Krzysztof Palczewski PhD, professor and chair of the department, served as senior author for the study.

The discovery digs into the biochemistry of vision and why the chemical configuration of the retinal is critical for humans to perceive light. Humans see with the help of an extremely sensitive protein in the back of the eye called rhodopsin, which attaches to a retinal molecule to sense light. Light photons enter the eye and get absorbed by the retinal-rhodopsin complex, activating a cascade of downstream signals that constitute vision. Importantly, the retinal awaits light photons while maintaining a particular chemical configuration -- 11-cis retinal -- and transforms into a second configuration -- all-trans retinal -- after it absorbs a light photon. But this transformation is a one-way ticket, and requires an army of specialized proteins to convert all-trans-retinal back to 11-cis-retinal. Inherited mutations in any of these specialized proteins can cause retinal degenerative diseases. Researchers who want to treat such diseases must repair or bypass the mutated proteins to maintain this retinal conversion in humans.

"Our study shows how a chemical modification in the retinal can activate downstream visual signaling in a photocyclic manner. This chemical modification allows retinal to self-renew using thermal energy, and hence does not require any additional enzymes," Gulati said.

The researchers discovered the self-renewing mechanism in bovine rhodopsin, which is exceptionally similar to human rhodopsin. The researchers used purified proteins in their laboratory to show that their modified retinal binds to bovine rhodopsin and successfully activates specific human eye proteins in response to light, and when complete, it uses thermal energy to slowly return to its inactive form that can be repeatedly reactivated with light. The findings suggest that retinal molecules with the specific chemical structure could reversibly stimulate rhodopsin that drives human vision.

Said Gulati, "Although one-way reaction mechanisms of GPCRs enable them to function normally in the human body, they cannot renew their activator molecules, and hence are dependent on continuous administration of drug molecules to treat disease symptoms. Controlled cyclic activation of GPCRs makes them self-sustainable."

The newly discovered mechanism may enhance current approaches to treat retinal degenerative diseases and other nerve cell disorders. Researchers can biochemically tinker with the retinal and the retinal-bound rhodopsin molecules to improve their ability to turn on and off proteins in the eye. Said Gulati, "Our next steps will be to design a new class of modified retinals with faster thermal recovery, and to test their efficiency as human therapeutic modalities."


Contents

Deficiency Edit

Vitamin A deficiency is estimated to affect approximately one third of children under the age of five around the world. [12] It is estimated to claim the lives of 670,000 children under five annually. [13] Between 250,000 and 500,000 children in developing countries become blind each year owing to vitamin A deficiency, with the highest prevalence in Africa and southeast Asia. [14] Vitamin A deficiency is "the leading cause of preventable childhood blindness", according to UNICEF. [15] [16] It also increases the risk of death from common childhood conditions such as diarrhea. UNICEF regards addressing vitamin A deficiency as critical to reducing child mortality, the fourth of the United Nations' Millennium Development Goals. [15]

Vitamin A deficiency can occur as either a primary or a secondary deficiency. A primary vitamin A deficiency occurs among children and adults who do not consume an adequate intake of provitamin A carotenoids from fruits and vegetables or preformed vitamin A from animal and dairy products. Early weaning from breastmilk can also increase the risk of vitamin A deficiency.

Secondary vitamin A deficiency is associated with chronic malabsorption of lipids, impaired bile production and release, and chronic exposure to oxidants, such as cigarette smoke, and chronic alcoholism. Vitamin A is a fat-soluble vitamin and depends on micellar solubilization for dispersion into the small intestine, which results in poor use of vitamin A from low-fat diets. Zinc deficiency can also impair absorption, transport, and metabolism of vitamin A because it is essential for the synthesis of the vitamin A transport proteins and as the cofactor in conversion of retinol to retinal. In malnourished populations, common low intakes of vitamin A and zinc increase the severity of vitamin A deficiency and lead physiological signs and symptoms of deficiency. [17] A study in Burkina Faso showed major reduction of malaria morbidity by use of combined vitamin A and zinc supplementation in young children. [18]

Due to the unique function of retinal as a visual chromophore, one of the earliest and specific manifestations of vitamin A deficiency is impaired vision, particularly in reduced light – night blindness. Persistent deficiency gives rise to a series of changes, the most devastating of which occur in the eyes. Some other ocular changes are referred to as xerophthalmia. First there is dryness of the conjunctiva (xerosis) as the normal lacrimal and mucus-secreting epithelium is replaced by a keratinized epithelium. This is followed by the build-up of keratin debris in small opaque plaques (Bitot's spots) and, eventually, erosion of the roughened corneal surface with softening and destruction of the cornea (keratomalacia) and leading to total blindness. [19] Other changes include impaired immunity (increased risk of ear infections, urinary tract infections, meningococcal disease), hyperkeratosis (white lumps at hair follicles), keratosis pilaris and squamous metaplasia of the epithelium lining the upper respiratory passages and urinary bladder to a keratinized epithelium. In relation to dentistry, a deficiency in vitamin A may lead to enamel hypoplasia.

Adequate supply, but not excess vitamin A, is especially important for pregnant and breastfeeding women for normal fetal development and in breastmilk. Deficiencies cannot be compensated by postnatal supplementation. [20] [21] Excess vitamin A, which is most common with high-dose vitamin supplements, can cause birth defects and therefore should not exceed recommended daily values. [22]

Vitamin A metabolic inhibition as a result of alcohol consumption during pregnancy is one proposed mechanism for fetal alcohol syndrome, and is characterized by teratogenicity resembling maternal vitamin A deficiency or reduced retinoic acid synthesis during embryogenesis. [23] [24] [25]

Vitamin A supplementation Edit

A 2012 review found no evidence that beta-carotene or vitamin A supplements increase longevity in healthy people or in people with various diseases. [27] A 2011 review found that vitamin A supplementation of children at risk of deficiency aged under five reduced mortality by up to 24%. [28] However, a 2016 and 2017 Cochrane review concluded there was not evidence to recommend blanket vitamin A supplementation for all infants less than a year of age, as it did not reduce infant mortality or morbidity in low- and middle-income countries. [29] [30] The World Health Organization estimated that vitamin A supplementation averted 1.25 million deaths due to vitamin A deficiency in 40 countries since 1998. [31]

While strategies include intake of vitamin A through a combination of breast feeding and dietary intake, delivery of oral high-dose supplements remain the principal strategy for minimizing deficiency. [32] About 75% of the vitamin A required for supplementation activity by developing countries is supplied by the Micronutrient Initiative with support from the Canadian International Development Agency. [33] Food fortification approaches are feasible, [34] but cannot ensure adequate intake levels. [32] Observational studies of pregnant women in sub-Saharan Africa have shown that low serum vitamin A levels are associated with an increased risk of mother-to-child transmission of HIV. Low blood vitamin A levels have been associated with rapid HIV infection and deaths. [35] [36] Reviews on the possible mechanisms of HIV transmission found no relationship between blood vitamin A levels in the mother and infant, with conventional intervention established by treatment with anti-HIV drugs. [37] [38]

Given that vitamin A is fat-soluble, disposing of any excess taken in through diet takes much longer than with water-soluble B vitamins and vitamin C. This allows for toxic levels of vitamin A to accumulate. These toxicities only occur with preformed vitamin A (retinoid). The carotenoid forms (for example, beta-carotene as found in carrots) give no such symptoms, but excessive dietary intake of beta-carotene can lead to carotenodermia, a harmless but cosmetically displeasing orange-yellow discoloration of the skin. [39] [40] [41]

In general, acute toxicity occurs at doses of 25,000 IU/kg of body weight, with chronic toxicity occurring at 4,000 IU/kg of body weight daily for 6–15 months. [42] However, liver toxicities can occur at levels as low as 15,000 IU (4500 micrograms) per day to 1.4 million IU per day, with an average daily toxic dose of 120,000 IU, particularly with excessive consumption of alcohol. [ citation needed ] In people with kidney failure, 4000 IU can cause substantial damage. Signs of toxicity may occur with long-term consumption of vitamin A at doses of 25,000–33,000 IU per day. [1]

Excessive vitamin A consumption can lead to nausea, irritability, anorexia (reduced appetite), vomiting, blurry vision, headaches, hair loss, muscle and abdominal pain and weakness, drowsiness, and altered mental status. In chronic cases, hair loss, dry skin, drying of the mucous membranes, fever, insomnia, fatigue, weight loss, bone fractures, anemia, and diarrhea can all be evident on top of the symptoms associated with less serious toxicity. [43] Some of these symptoms are also common to acne treatment with Isotretinoin. Chronically high doses of vitamin A, and also pharmaceutical retinoids such as 13-cis retinoic acid, can produce the syndrome of pseudotumor cerebri. [44] This syndrome includes headache, blurring of vision and confusion, associated with increased intracerebral pressure. Symptoms begin to resolve when intake of the offending substance is stopped. [45]

Chronic intake of 1500 RAE of preformed vitamin A may be associated with osteoporosis and hip fractures because it suppresses bone building while simultaneously stimulating bone breakdown, [46] although other reviews have disputed this effect, indicating further evidence is needed. [1]

A 2012 systematic review found that beta-carotene and higher doses of supplemental vitamin A increased mortality in healthy people and people with various diseases. [27] The findings of the review extend evidence that antioxidants may not have long-term benefits.

As some carotenoids can be converted into vitamin A, attempts have been made to determine how much of them in the diet is equivalent to a particular amount of retinol, so that comparisons can be made of the benefit of different foods. The situation can be confusing because the accepted equivalences have changed.

For many years, a system of equivalencies in which an international unit (IU) was equal to 0.3 μg of retinol (

1 nmol), 0.6 μg of β-carotene, or 1.2 μg of other provitamin-A carotenoids was used. [47] This relationship is alternatively expressed by the retinol equivalent (RE): one RE corresponded to 1 μg retinol, 2 μg β-carotene dissolved in oil (it is only partly dissolved in most supplement pills, due to very poor solubility in any medium), 6 μg β-carotene in normal food (because it is not absorbed as well as when in oils), and 12 μg of either α-carotene, γ-carotene, or β-cryptoxanthin in food. [48]

Newer research has shown that the absorption of provitamin-A carotenoids is only half as much as previously thought. As a result, in 2001 the US Institute of Medicine recommended a new unit, the retinol activity equivalent (RAE). Each μg RAE corresponds to 1 μg retinol, 2 μg of β-carotene in oil, 12 μg of "dietary" beta-carotene, or 24 μg of the three other dietary provitamin-A carotenoids. [49]

Because the conversion of retinol from provitamin carotenoids by the human body is actively regulated by the amount of retinol available to the body, the conversions apply strictly only for vitamin A-deficient humans. [ citation needed ] The absorption of provitamins depends greatly on the amount of lipids ingested with the provitamin lipids increase the uptake of the provitamin. [50]

A sample vegan diet for one day that provides sufficient vitamin A has been published by the Food and Nutrition Board (page 120 [49] ). Reference values for retinol or its equivalents, provided by the National Academy of Sciences, have decreased. The RDA (for men) established in 1968 was 5000 IU (1500 μg retinol). In 1974, the RDA was revised to 1000 RE (1000 μg retinol). As of 2001, the RDA for adult males is 900 RAE (900 μg or 3000 IU retinol). [ citation needed ] By RAE definitions, this is equivalent to 1800 μg of β-carotene supplement dissolved in oil (3000 IU) or 10800 μg of β-carotene in food (18000 IU).

The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for vitamin A in 2001. For infants up to 12 months there was not sufficient information to establish a RDA, so Adequate Intake (AI) shown instead. As for safety the IOM sets tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs). The calculation of retinol activity equivalents (RAE) is each μg RAE corresponds to 1 μg retinol, 2 μg of β-carotene in oil, 12 μg of "dietary" beta-carotene, or 24 μg of the three other dietary provitamin-A carotenoids. [49]

Life stage group US RDAs or AIs (μg RAE/day) Upper limits (UL, μg/day) [IOM 1]
Infants 0–6 months 400 (AI) 500 (AI)
7–12 months 600 600
Children 1–3 years 300 600
4–8 years 400 900
Males 9–13 years 600 1700
14–18 years 900 2800
>19 years 900 3000
Females 9–13 years 600 1700
14–18 years 700 2800
>19 years 700 3000
Pregnancy <19 years 750 2800
>19 years 770 3000
Lactation <19 years 1200 2800
>19 years 1300 3000

  1. ^ ULs are for natural and synthetic retinol ester forms of vitamin A. Beta-carotene and other provitamin A carotenoids from foods and dietary supplements are not added when calculating total vitamin A intake for safety assessments, although they are included as RAEs for RDA and AI calculations. [1][49]

For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For vitamin A labeling purposes 100% of the Daily Value was set at 5,000 IU, but it was revised to 900 μg RAE on 27 May 2016. [51] [52] Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers with US$10 million or more in annual food sales, and by 1 January 2021 for manufacturers with lower volume food sales. [53] [54] A table of the old and new adult daily values is provided at Reference Daily Intake.

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL defined the same as in United States. For women and men of ages 15 and older, the PRIs are set respectively at 650 and 750 μg RE/day. PRI for pregnancy is 700 μg RE/day, for lactation 1300/day. For children of ages 1–14 years, the PRIs increase with age from 250 to 600 μg RE/day. These PRIs are similar to the U.S. RDAs. [55] The EFSA reviewed the same safety question as the United States, and set a UL at 3000 μg/day for preformed vitamin A. [56]

Vitamin A is found in many foods, including the following list. [57] Conversion of carotene to retinol varies from person to person, and bioavailability of carotene in food varies. [58] [59]

Source Retinol activity equivalences
(RAEs), μg/100g
cod liver oil 30000
liver turkey 8058
liver beef, pork, fish 6500
liver chicken 3296
ghee 3069
sweet potato [food 1] 961
carrot 835
broccoli leaf 800
butter 684
kale 681
collard greens frozen then boiled 575
butternut squash 532
dandelion greens 508
spinach 469
pumpkin 426
collard greens 333
cheddar cheese 265
cantaloupe melon 169
bell pepper/capsicum, red 157
egg 140
apricot 96
papaya 55
tomatoes 42
mango 38
pea 38
broccoli florets 31
milk 28
bell pepper/capsicum, green 18
spirulina 3

Vitamin A plays a role in a variety of functions throughout the body, [4] [60] such as:

  • Vision
  • Gene transcription
  • Immune function
  • Embryonic development and reproduction
  • Bone metabolism
  • Skin and cellular health

Vision Edit

The role of vitamin A in the visual cycle is specifically related to the retinal form. Within the eye, 11-cis-retinal is bound to the protein "opsin" to form rhodopsin in rods [6] and iodopsin (cones) at conserved lysine residues. As light enters the eye, the 11-cis-retinal is isomerized to the all-"trans" form. The all-"trans" retinal dissociates from the opsin in a series of steps called photo-bleaching. This isomerization induces a nervous signal along the optic nerve to the visual center of the brain. After separating from opsin, the all-"trans"-retinal is recycled and converted back to the 11-"cis"-retinal form by a series of enzymatic reactions. In addition, some of the all-"trans" retinal may be converted to all-"trans" retinol form and then transported with an interphotoreceptor retinol-binding protein (IRBP) to the pigment epithelial cells. Further esterification into all-"trans" retinyl esters allow for storage of all-trans-retinol within the pigment epithelial cells to be reused when needed. [17] The final stage is conversion of 11-cis-retinal will rebind to opsin to reform rhodopsin (visual purple) in the retina. Rhodopsin is needed to see in low light (contrast) as well as for night vision. Kühne showed that rhodopsin in the retina is only regenerated when the retina is attached to retinal pigmented epithelium, [6] which provides retinal. It is for this reason that a deficiency in vitamin A will inhibit the reformation of rhodopsin, and will lead to one of the first symptoms, night blindness. [61]

Gene transcription Edit

Vitamin A, in the retinoic acid form, plays an important role in gene transcription. Once retinol has been taken up by a cell, it can be oxidized to retinal (retinaldehyde) by retinol dehydrogenases retinaldehyde can then be oxidized to retinoic acid by retinaldehyde dehydrogenases. [22] The conversion of retinaldehyde to retinoic acid is an irreversible step this means that the production of retinoic acid is tightly regulated, due to its activity as a ligand for nuclear receptors. [17] The physiological form of retinoic acid (all-trans-retinoic acid) regulates gene transcription by binding to nuclear receptors known as retinoic acid receptors (RARs) which are bound to DNA as heterodimers with retinoid "X" receptors (RXRs). RAR and RXR must dimerize before they can bind to the DNA. RAR will form a heterodimer with RXR (RAR-RXR), but it does not readily form a homodimer (RAR-RAR). RXR, on the other hand, may form a homodimer (RXR-RXR) and will form heterodimers with many other nuclear receptors as well, including the thyroid hormone receptor (RXR-TR), the Vitamin D3 receptor (RXR-VDR), the peroxisome proliferator-activated receptor (RXR-PPAR) and the liver "X" receptor (RXR-LXR). [62]

The RAR-RXR heterodimer recognizes retinoic acid response elements (RAREs) on the DNA whereas the RXR-RXR homodimer recognizes retinoid "X" response elements (RXREs) on the DNA although several RAREs near target genes have been shown to control physiological processes, [22] this has not been demonstrated for RXREs. The heterodimers of RXR with nuclear receptors other than RAR (i.e. TR, VDR, PPAR, LXR) bind to various distinct response elements on the DNA to control processes not regulated by vitamin A. [17] Upon binding of retinoic acid to the RAR component of the RAR-RXR heterodimer, the receptors undergo a conformational change that causes co-repressors to dissociate from the receptors. Coactivators can then bind to the receptor complex, which may help to loosen the chromatin structure from the histones or may interact with the transcriptional machinery. [62] This response can upregulate (or downregulate) the expression of target genes, including Hox genes as well as the genes that encode for the receptors themselves (i.e. RAR-beta in mammals). [17]

Immune function Edit

Vitamin A plays a role in many areas of the immune system, particularly in T cell differentiation and proliferation. [63] [64]

Vitamin A promotes the proliferation of T cells through an indirect mechanism involving an increase in IL-2. [64] In addition to promoting proliferation, vitamin A (specifically retinoic acid) influences the differentiation of T cells. [65] [66] In the presence of retinoic acid, dendritic cells located in the gut are able to mediate the differentiation of T cells into regulatory T cells. [66] Regulatory T cells are important for prevention of an immune response against "self" and regulating the strength of the immune response in order to prevent host damage. Together with TGF-β, Vitamin A promotes the conversion of T cells to regulatory T cells. [65] Without Vitamin A, TGF-β stimulates differentiation into T cells that could create an autoimmune response. [65]

Hematopoietic stem cells are important for the production of all blood cells, including immune cells, and are able to replenish these cells throughout the life of an individual. Dormant hematopoietic stem cells are able to self-renew, and are available to differentiate and produce new blood cells when they are needed. In addition to T cells, Vitamin A is important for the correct regulation of hematopoietic stem cell dormancy. [67] When cells are treated with all-trans retinoic acid, they are unable to leave the dormant state and become active, however, when vitamin A is removed from the diet, hematopoietic stem cells are no longer able to become dormant and the population of hematopoietic stem cells decreases. [67] This shows an importance in creating a balanced amount of vitamin A within the environment to allow these stem cells to transition between a dormant and activated state, in order to maintain a healthy immune system.

Vitamin A has also been shown to be important for T cell homing to the intestine, effects dendritic cells, and can play a role in increased IgA secretion, which is important for the immune response in mucosal tissues. [63] [68]

Dermatology Edit

Vitamin A, and more specifically, retinoic acid, appears to maintain normal skin health by switching on genes and differentiating keratinocytes (immature skin cells) into mature epidermal cells. [69] Exact mechanisms behind pharmacological retinoid therapy agents in the treatment of dermatological diseases are being researched. For the treatment of acne, the most prescribed retinoid drug is 13-cis retinoic acid (isotretinoin). It reduces the size and secretion of the sebaceous glands. Although it is known that 40 mg of isotretinoin will break down to an equivalent of 10 mg of ATRA — the mechanism of action of the drug (original brand name Accutane) remains unknown and is a matter of some controversy. Isotretinoin reduces bacterial numbers in both the ducts and skin surface. This is thought to be a result of the reduction in sebum, a nutrient source for the bacteria. Isotretinoin reduces inflammation via inhibition of chemotactic responses of monocytes and neutrophils. [17] Isotretinoin also has been shown to initiate remodeling of the sebaceous glands triggering changes in gene expression that selectively induce apoptosis. [70] Isotretinoin is a teratogen with a number of potential side-effects. Consequently, its use requires medical supervision.

Retinal/retinol versus retinoic acid Edit

Vitamin A-deprived rats can be kept in good general health with supplementation of retinoic acid. This reverses the growth-stunting effects of vitamin A deficiency, as well as early stages of xerophthalmia. However, such rats show infertility (in both male and females) and continued degeneration of the retina, showing that these functions require retinal or retinol, which are interconvertible but which cannot be recovered from the oxidized retinoic acid. The requirement of retinol to rescue reproduction in vitamin A deficient rats is now known to be due to a requirement for local synthesis of retinoic acid from retinol in testis and embryos. [71] [72]

Retinyl palmitate has been used in skin creams, where it is broken down to retinol and ostensibly metabolised to retinoic acid, which has potent biological activity, as described above. The retinoids (for example, 13-cis-retinoic acid) constitute a class of chemical compounds chemically related to retinoic acid, and are used in medicine to modulate gene functions in place of this compound. Like retinoic acid, the related compounds do not have full vitamin A activity, but do have powerful effects on gene expression and epithelial cell differentiation. [73] Pharmaceutics utilizing megadoses of naturally occurring retinoic acid derivatives are currently in use for cancer, HIV, and dermatological purposes. [74] At high doses, side-effects are similar to vitamin A toxicity. [75]

The discovery of vitamin A may have stemmed from research dating back to 1816, when physiologist François Magendie observed that dogs deprived of nutrition developed corneal ulcers and had a high mortality rate. [76] In 1912, Frederick Gowland Hopkins demonstrated that unknown accessory factors found in milk, other than carbohydrates, proteins, and fats were necessary for growth in rats. Hopkins received a Nobel Prize for this discovery in 1929. [76] [77] By 1913, one of these substances was independently discovered by Elmer McCollum and Marguerite Davis at the University of Wisconsin–Madison, and Lafayette Mendel and Thomas Burr Osborne at Yale University, who studied the role of fats in the diet. McCollum and Davis ultimately received credit because they submitted their paper three weeks before Mendel and Osborne. Both papers appeared in the same issue of the Journal of Biological Chemistry in 1913. [78] The "accessory factors" were termed "fat soluble" in 1918 and later "vitamin A" in 1920. In 1919, Harry Steenbock (University of Wisconsin–Madison) proposed a relationship between yellow plant pigments (beta-carotene) and vitamin A. In 1931, Swiss chemist Paul Karrer described the chemical structure of vitamin A. [76] Vitamin A was first synthesized in 1947 by two Dutch chemists, David Adriaan van Dorp and Jozef Ferdinand Arens.

During World War II, German bombers would attack at night to evade British defenses. In order to keep the 1939 invention of a new on-board Airborne Intercept Radar system secret from German bombers, the British Ministry of Information told newspapers that the nighttime defensive success of Royal Air Force pilots was due to a high dietary intake of carrots rich in vitamin A, propagating the myth that carrots enable people to see better in the dark. [79]


7. Unsaturated Fats

In chemistry, fats are the ester of fatty acids or a mixture of such compounds. The molecule of a fatty acid consists of a carboxyl group HO(O=)C− connected to an unbranched alkyl group – (_)_ . The difference between saturated and unsaturated fats is that the former only have single bond hydrocarbon chains, while the latter has at least one double bond in the hydrocarbon chain. Due to the presence of double bonds, unsaturated fatty acids exhibit geometrical isomerism, which depends on the orientation of groups around the double bond. The designation “cis” means that the acyl chains are on the same side. Whereas, “trans” means the acyl chains are on the opposite side of the double bond. Unsaturated fatty acids can exist in either the cis or trans form depending on the configuration of the hydrogen atoms attached to the carbon atoms joined by the double bonds. Under conditions of partial hydrogenation, a double bond may change from a cis to a trans configuration (geometric isomerization) or move to other positions in the carbon chain (positional isomerization). Both types of isomerization frequently occur in any fatty acid undergoing hydrogenation.


Sources

  • www.researchgate.net/…/Visual-cycle-Absorption-of-light-by-visual-pigments-rhodopsin-or-cone-opsin-causes_fig2_249648159
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1360213/
  • https://www.ncbi.nlm.nih.gov/pubmed/21447403
  • www.nobelprize.org/…/wald-lecture.html
  • https://pubs.acs.org/doi/10.1021/cr400107q#
  • http://www.who.int/nutrition/topics/vad/en/
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1088937/