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Low Molecular Weight Peptides

K. L. Reichelt

1 2 3 4 5 5.1 5.2 5.3 5.4 6 7

Special Aspects of Oligopeptide Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402 Peptide Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403 Is There a General Role of Peptides in the Brain? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403 Peptide Purification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 Endogenous Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405 Pyroglutamate Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406 gGlutamyl Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406 Diketopiperazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406 Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407 Exogenous Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408

Springer-Verlag Berlin Heidelberg 2007

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Abstract: Peptides active in the central nervous system (CNS) may be endogenous or exogenous. NTerminally substituted peptides have higher lipid membrane penetration properties, and the main category of such peptides is Nacetyl and pyroglu peptides. Though probably also transmitters, most peptides apparently seem to be neuromodulators and are often released differently from traditional transmitters. Peptides are frequently colocated with monoamines, amino acid transmitters, and acetylcholine in the synapse. Peptides show pronounced ability to bind to other molecules, and solely immunoassays (immunelike) do not prove the presence of any given peptide. Mass spectrometry is the method of choice today. Peptides usually show hormetic doseresponse curves and are often active in picomolar concentrations. List of Abbreviations: CCK, Cholecystokinin; DSIP, Delta sleep inducing peptide; GABA, Gamma amino butyric acid; GSH, Glutathione (reduced form); MIF, Melanocyte-stimulating hormone-release inhibiting factor (P-L-GNH2); TFA, Triuoroacetic acid; TRH, Thyrotropin releasing hormone

Special Aspects of Oligopeptide Biology

Peptides are ampholytes and depending on pH their electric charge changes (> Figure 161). Their afnity for lipids increases with the chain length and also with the side groups of aromatic or aliphatic characters. Low molecular weight peptides are here arbitrarily taken to be peptides up to 12 amino acids in length. The peptides found in brain may be endogenous (formed locally) or exogenous (imported from outside the brain).

. Figure 161 The different pHdependent states of ionization of peptides. The R side chains can be aliphatic or aromatic. The latter will increase the HPLC retention time and the afnity for lipid membranes

Unfortunately a lot of work on peptides has been mainly based on immunological techniques and the immunelike prex is often forgotten. Other techniques to conrm the nature of any given peptide are important: highpressure liquid chromatography (HPLC) with spiking and mass spectrometry (MS) (the nal arbiter with MS/MS techniques causing fragmentation). With MALDI TOF or electron spray MS, the sequences can be obtained directly. The Nterminal amino acid determination with and without sequencing is very useful. Antibodies raised against different parts of the peptide have also been used in an attempt to bypass the limitations of immune techniques, but are not completely safe. Immuno like rkmans groove does not guarantee identity. Although peptides often are epitopes (signals binding to Bjo causing antibody formation), the code is quite degenerate. Work with peptides has been difcult for several reasons. First, they show an almost impossible tendency to form aggregates and bind noncovalently to proteins (Walter et al., 1978; Kastin et al., 1984; Burhol et al., 1986; Menezo and Khatchaturian, 1986; Rocetti et al., 1988; Gianfranceschi et al., 1994; Elgjo and Reichelt, 2004) and together with amino acids also to aminoglycans (Stadler and Whittaker, 1978). Interaction with phospholipids and membranes has been described for opioid peptides (Alsina et al., 1991), and demonstration of the presence of a peptide in a membrane could also be an artifact due to this phenomenon. Thus, unexpected high levels of opioid peptides were found in rat membranes (Rothman et al., 1987) and peptide drugs can form highmolecular weight forms in vivo (Hori et al., 1984).

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Almost all peptides show bellshaped dose responses or hormesis (Calabrese, 2001; Calabrese and Baldwin, 2001; 2003). This has proved to be rather exasperating during purication and testing because extensive dilution series must be run from 106 to 1012 M. In aqueous solutions and at the waterglass interface stability problems remain a problem (Bell, 1997), and polypropanol plastic containers/test tubes and the dried form of the peptides are preferable for storage. Peptides are also good inhibitors of peptide breakdown and may therefore have indirect effects by potentiating endogenous peptide activity by means of protecting them from breakdown (La Bella et al., 1985). Thus, the effects of adding a peptide may be indirect by prevention of the breakdown of endogenous peptides. Two peptides given simultaneously can result in cooperative effects by complex formation or protection against breakdown or both (Kastin et al., 2002). Peptides that contain SH groups at pH greater than 6 start forming mixed disuldes. At pH values higher than 7 this is quite fast and mixed disuldes may arise with any SHcontaining peptides and proteins. At higher pH, sulfonic acids may also be formed and peptide bonds may also move from the a to the b position in aspartic acid. Strongly alkaline conditions may also split some peptide bonds like AspSer. Finally, chelating different metals may change the activity of peptides as shown for thyroliberin (TRH, thyrotropinreleasing hormone) (Tonoue et al., 1979).

Peptide Formation

There are three distinct routes of peptide synthesis in the brain: (1) ribosomal protein synthesis and specic splitting of a peptide, depending on peptidases and glycosylation of the precursor proteins (Loh and Gainer, 1979), (2) direct peptide synthesis by phosphorylation of the involved amino acids, and (3) amino acid or peptide transfer. (1) An example of the rst alternative is TRH and opioids like metenkephalin and leuenkephalin as well as cholecystokinin (CCK). Different prepeptides are frequently found to give rise to families of peptides with different chain lengths and often with different breakdown patterns in different tissues (Rehfeld et al., 2003). The enzymes involved in cutting out the active peptides from precursor proteins are convertase1 and 2 (Rehfeld et al., 2003). Peptide fragments also have neuroactive roles (Hallberg and Nyberg, 2003). It is well known that sulfation, phosphorylation, glucosylation, and amidation can give rise to additional derivatives of the main peptide, and intramolecular disulde bonds can cause considerable conformational specicity. Transglutaminase can further form pseudopeptide bonds between glutamine and lysine and attachment to different proteins and peptides. Also, esterication of fatty acids to the hydroxyl groups is possible in threonine and serinecontaining peptides and also binding to the Nterminal amine group (Shoji et al., 1986). (2) Direct synthesis from amino acids: both glutathione (GSH) and peptides such as carnosine (balanyl histidine) and acetylaspartylglutamate are apparently synthesized directly by specic enzymes. (3) Amino acid transfer: GSH can transfer its glutamate to amino acids and peptides and form a series of gglutamyl peptides (> Table 162). Because the reduced form GSH is the active peptide involved, this couples the uptake of amino acids and peptides to the redox state in the cells. Peptide leukotrienes are also formed by the group transfer (Shaw and Krell, 1991). Nucleotide peptides have been found in the liver but have not been studied in brain tissues.

Is There a General Role of Peptides in the Brain?

It seems that peptides are sometimes transmitters but often also act as modulators of neuronal activity. It is not easy to tell which is which in practice. However, it seems that peptides act more often by modulating transmitter uptake, release, and synthesis and also the ring frequency (Barker, 1976). Examples are typically represented by the endogenous pentapeptide QYNAD, which blocks Na channels (Meuth et al., 2003), and the tripeptide amide pyroEWGNH2, which stimulates serotonin

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uptake into CHO ovarian cells transfected with human gene for the serotonin transporter (Keller, 1997). The peptide also increases serotonin levels in rat brain synapses. This is also reected in the more global effects of peptides on behavior (FehmWolfdorf and Born, 1991). Thus, CCK 14 can induce a paniclike reaction (De Montigny, 1989), facilitate serotonin release in the rat hypothalamus (Voigt et al., 1998), accelerate the habituation rate to a novel environment (Crawley, 1984), affect memory in rats (Harro and Oreland, 1993), and play a role in satiety (Zhang et al., 1986). This seems to conrm the old paradigm that nature is conservative with regard to structure, but radical to function. This is illustrated by vasopressin, which has neuromodulating effects (Brinton et al., 2000), and oxytocin, related to emotional behavior (Pittman and Spencer, 2005; Matsuoka et al., 2005). Serotoninmoduline is likewise an endogenous peptide involved in control of anxiety (Grimaldi et al., 1999) and serotonin activity (Massot et al., 1996). Tyr WMif induces Fos antigen as a potent analogue of YPWGNH2 (Liso et al., 1994) in several nuclei of the brain, and complex behavior is induced by the egg laying hormone in Aplysia (Bernheim and Mayeri, 1995), indicating that more modulating roles are probable. Because peptides are often released by higherfrequency stimulation than most conventional transmit kfelt, 1983; ters (Han, 2003; and references therein) and they coexist in the synapse (Lundberg and Ho kfelt, 1991), all of Forloni et al., 1987; Nusbaum et al., 2001), often with presynaptic inhibitory activity (Ho this strengthens the view that they are more often neuromodulators rather than traditional neurotransmitters. Thus, a series of small dipeptides modulate GABAergic and glutamatergic transmission (Varga et al., 1988, 1994).

Peptide Purication

Because immune data need conrmation, a short outline of peptide purication is presented below. Usually the purication is initiated because of biological activity or an antibodybinding compound is found. If one is looking for a known molecular weight (MW) peptide, this may also guide the purication. Roughly, the steps outlined below can be followed for purication (Pedersen et al., 1999); whenever possible, saltcontaining buffers are avoided. They are not easily removed because of the attachment to peptides. It is also of advantage to stick to acidic buffers whenever possible because of alkaline problems, in particular if SH groups are involved, and basic conditions also quickly deamidate peptides. In short, the following steps are common: (1) G25 gel ltration in 1 M acetic acid to separate lowMW compounds from highMW compounds (we use 0.9 90 cm columns). (2) Gel ltration in 0.5 M acetic acid on P2 gel columns (1.6 90 cm and ow rate of 4 ml/10 min) to separate small and large peptides. (3) Batch separation on a cation exchanger in the H form where nonprotonable compounds (mainly N terminally blocked peptides) pass through and protonable compounds (aminofree peptides) are retained and eluted with 2 M NH3. (4) Anion exchange with a column in the acetate form in batch to separate neutral from acidic peptides, and elution with water followed by 2 M acetic acid. (5) C18 reversephase batch separation hlen et al. 1980. (6) Fractogel MG of amino acids, ammonia, and salts, etc., from peptides as described in Bo 2000 in 1 M acetic acid and 40 mM HCl and offline ninhydrin coloring after hydrolysis for approximate MW determination. (7) C18 reversephase HPLC using gradients of triuoroacetic acid (TFA) against acetonitrile and the absorption read at 215 nm. When peptides contain aromatic groups, methanol can also be used as an organic phase and monitored at 280 nm. (8) Normal phase with acetonitrile and increasing the water gradient from 5% to 32% over 30 min at a ow rate of 1 ml/min using TSK amide80 columns (25 0.24 cm) (Tosoh, Japan) is performed. UV monitoring of highpressure runs is done at 215 and 280 nm. When we nd one Nterminal and/or one Cterminal amino acid, the peptide is considered probably pure. NSubstituted peptides were usually subjected to anion exchange starting with 0.01 M formic acid and increasing the concentration of formic acid to 0.5 M. NAminofree peptides separated with reverse phase HPLC as described above. Offline peptide monitoring (in particular, after gel ltration) is best done using 2 M alkaline hydrolysis in an aliquot in boiling water for 2 h, neutralizing with HCl, and ninhydrin coloring in an acetatecyanide

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buffer where each amino acid has the same molecular absorption coefcient, thereby tryptophan is not destroyed. The reaction is stopped after 15 min boiling with isopropanol/water and read at 570 nm. The method has the advantage of increasing the sensitivity of the assay by splitting many peptide bonds (Reichelt and Kvamme, 1973).

Endogenous Peptides

These peptides can roughly be divided into N terminally blocked peptides and aminofree peptides (protonable peptides). Peptides that are Nsubstituted but with protonable side groups like lysine will behave as ordinary peptides, even if N terminally blocked. The group of N terminally blocked peptides consists mainly of Nacyl, pyroglutamyl and cyclic peptides (diketopiperazines). NAcetyl peptides are mostly acetylaspartyl derivatives and the most abundant peptide in the brain is acetylaspartylglutamate, which is found up to 0.28 m moles/g brain tissue. This peptide is probably formed hdesma ki and Timonen, 1982; Cangro by a nonribosomal mechanism (Reichelt and Kvamme, 1973; La et al., 1987) and has been suspected of being a possible transmitter. A series of acetylaspartyl peptides could be formed from different amino acids (Reichelt and Kvamme, hdesma ki and Timonen, 1982) and the presence of such peptides was conrmed by MS (> Table 161) 1973; La hdesma ki, 1983; Marnela et al., 1984). We proposed that they might be shortterm memory (Marnela and La

. Table 161 gGlutamyl peptides and peptoids Monkey brain Reichelt (1970) GluGlu GluGln GluAla GluIle GluSer GluAlaGly GluCysGly
a

Ox brain Sano et al. (1966) GluGlu GluGln GluAlaAIB GluSer GluAla GluVal GluMetCysGly GluCysGly

Others GluTaua GluAspb Gluhistaminec Gludopamined

Nakamura et al. (1990) Cheung and Lim (1979) c Weinreich (1979) d McCaman et al. (1985) AIB, aminoisobutyric acid
b

substrates reecting the sequence of impinging signals on the integrating neuron (Reichelt et al., 1982). Furthermore, the formation of less hydrophilic peptides could ease the reuptake of electrically charged transmitters like amino acids into synaptosomes. In spite of the slow in vivo metabolism of acetylaspartate (Jacobson, 1959; Reichelt and Kvamme, 1967), the absence of acetylaspartatesplitting acetylase causes a massive loss of Nacetylaspartate in the urine (Canavans syndrome) and also an almost complete absence of synapse formation (Gordon, 2001). This may be indicative of an essential role of Nacetylaspartic acid in the formation and/or maintenance of synapses.

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5.1 Pyroglutamate Peptides


The most well known of these peptides are TRH and folliliberin (FSH, folliclestimulating releasing hormone), which has also other functions, affecting the function of different parts of the CNS and being related to depression (Kirkegaard et al., 1979; Banki et al., 1988). Most of the hypothalamicreleasing peptides are Nterminal pyroglutamate compounds, which probably confers some peptidase resistance of these peptides. In > Table 162, a few pyroglu peptides, recently reviewed by Reichelt (2006), are listed. In many tissues

. Table 162 NSubstituted peptides NAcetyl substituted peptides AcDEa AcDGSa AcDEGa AcDEDa AcDDa AcD (tau,tau)a Pyroglu peptides PyroEHPNH2 (TRH) PyroEHWSYGLRPNH2 (LHRH)
a b

AcDE AcDtaub AcDEtaub AcEtaub AcAADISQWAGPLc Cyclic peptides HP GF

Reichelt and Kvamme (1973) hdesma ki (1983) Marnela and La c Hippocampal cholinergic neurostimulating peptide PyroE, pyroglutamyl; TRH, thyroliberin (thyrotropinreleasing hormone); LHRH, luliberin (luteinizing hormonereleasing hormone)

pyroglu peptides are growthregulating entities acting by means of feedback inhibition (Elgjo and Reichelt, 2004) as demonstrated in hematopoietic (Paukovits and Laerum, 1983) and thymic cells (Gianfranceschi et al., 1994).

5.2 gGlutamyl Peptides


These peptides are also relatively abundant and may well reect amino acid /peptide transport into neurons and/or glia by means of the gglutamyl cycle (Grifth et al., 1979). For an overview, see > Table 161 (Sano et al., 1966; Reichelt, 1970). The gglutamyl cycle has the advantage of coupling amino acid uptake to the redox potential of the cell because GSH reects the level of reductive potential (Sir Hans Krebs, personal communication). The more polar amino acids are also rendered more hydrophobic when their amino groups are blocked, thus facilitating their uptake across membranes, independently of the transport proteins.

5.3 Diketopiperazines
Diketopiperazines or cyclic peptides also show high afnity for other compounds (Gisin et al., 1978). The cyclic dipeptide HP split from TRH forms such a cyclic peptide, having many different effects in the CNS.

Low molecular weight peptides . Table 163 Some small opioid peptides Kyotorphin Neokyotorphin Metenkephalin Leuenkephalin Endorphin 1 Endorphin 2

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YR TSKYR YGGFM YGGFL YPWGNH2 YPFFNH2

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. Table 164 Some very small peptides with unknown/uncertain function GABAH GABAK GABA(CH)H bAK bA (CH3)H bAH (carnosine) DS AF IL Pisano et al. (1961)

Kumon et al. (1970)

Versteeg and Witter (1970)

. Table 165 Other small peptides, with presence in the CNS properly demonstrated Neuropeptide FF Neuropeptide SF Substance P DSIP Angiotensin I Angotensin II Cholecystokinin (CCK) 14 Gastrin tetrapeptide Oxytocin Vasopressin (arginine) Vasopressin (lysine) Melanocytestimulating hormone releaseinhibiting factor 5HT moduline TRHpotentiating peptide
DSIP, dsleepinducing peptide (Schoenenberger et al., 1978) In oxytocin and vasopressin, the two cysteines are joined by a disulde bond 5HT, serotonin; TRH, thyroliberin

FLFQPQRFNH2 SQAFLFQPQPFNH2 RPKPQQFFGLMNH2 WAGGDASGE DRVYIHPFHL DRVYIHPF DYMG WMDFNH2 CYIQNCPLGNH2 CYFQNCPRGNH2 CYFQNCPKGNH2 PLGNH2 LSAL SFMESDVT

5.4 Opioids
The small opioid peptides like metenkephalin and leuenkephalin are both found in the CNS, although MS has been sparingly used to prove their existence. Other lowmolecular opioid peptides found are given in

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163. Opioids not only facilitate dopaminergic transmission by inhibiting dopamine uptake (Hole et al., 1979) but also inhibit GABAmediated transmission (Vaughan et al., 1997). Discussions of bendorphinsized peptides are found in other chapters of this handbook.

Exogenous Peptides

The uptake of peptides is usually limited, but the Nsubstitution renders peptides more olenic, and therefore increases uptake. Furthermore, the formation of glycopeptides, e.g. opioids, increases uptake (Egleton et al., 2005). LowMW opioids are taken up across the bloodbrain barrier (Ermisch et al., 1983, Banks et al., 1996) and interestingly exorphins formed in the gut from casein can penetrate this barrier as well (Nyberg et al., 1989) and induce Fos antigen in several important nuclei of the brain (Sun et al., 1999). Also, behavioral effects (Sun and Cade, 1999) similar to those seen with intracranioventricularly injected opioid from urine of patients with schizophrenia (Hole et al., 1979; Drysdale et al., 1982; Cade et al., 2000) are seen. The fact that peptides are often active at nanomolar to picomolar concentrations may have vast consequences in neuropsychiatric diseases, where the guttobrain axis seems to be important, as described in the autistic syndromes (Reichelt and Knivsberg, 2003). The effect of feeding in infectious bowel disease (Geissler et al., 1995; Hart et al., 1998), causing widespread scattered edema in the white matter seen by means of nuclear magnetic resonance (NMR), points to a fairly intimate relationship of the gut to the brain.

Summary

Peptides should be nowadays studied not only using immune techniques but also techniques preferably supplemented with MS or other independent techniques. There is reasonably strong evidence indicating that small peptides are mostly neuromodulators rather than traditional neurotransmitters. The tendency for peptides to form complexes with peptides and proteins as well as membranes may cause problems during identication and subcellular distribution studies.

References
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